CN101481323B - Benzo cyclohepten derivate, and preparation and medical use thereof - Google Patents

Benzo cyclohepten derivate, and preparation and medical use thereof Download PDF

Info

Publication number
CN101481323B
CN101481323B CN2008100006483A CN200810000648A CN101481323B CN 101481323 B CN101481323 B CN 101481323B CN 2008100006483 A CN2008100006483 A CN 2008100006483A CN 200810000648 A CN200810000648 A CN 200810000648A CN 101481323 B CN101481323 B CN 101481323B
Authority
CN
China
Prior art keywords
aminomethyl phenyl
dihydro
phenyl
benzo ring
methane amide
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
CN2008100006483A
Other languages
Chinese (zh)
Other versions
CN101481323A (en
Inventor
李松
刘瑶
苏靖
肖军海
王莉莉
钟武
郑志兵
谢云德
李行舟
赵国明
王晓奎
周辛波
刘洪英
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Institute of Pharmacology and Toxicology of AMMS
Original Assignee
Institute of Pharmacology and Toxicology of AMMS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Institute of Pharmacology and Toxicology of AMMS filed Critical Institute of Pharmacology and Toxicology of AMMS
Priority to CN2008100006483A priority Critical patent/CN101481323B/en
Priority to PCT/CN2009/000040 priority patent/WO2009092284A1/en
Publication of CN101481323A publication Critical patent/CN101481323A/en
Application granted granted Critical
Publication of CN101481323B publication Critical patent/CN101481323B/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/06—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/57—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C233/60—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
    • C07D313/02—Seven-membered rings
    • C07D313/06—Seven-membered rings condensed with carbocyclic rings or ring systems
    • C07D313/08—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/12—One of the condensed rings being a six-membered aromatic ring the other ring being at least seven-membered

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Pulmonology (AREA)
  • Diabetes (AREA)
  • Communicable Diseases (AREA)
  • Virology (AREA)
  • Dermatology (AREA)
  • Rheumatology (AREA)
  • Urology & Nephrology (AREA)
  • Oncology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Emergency Medicine (AREA)
  • Vascular Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Obesity (AREA)
  • AIDS & HIV (AREA)
  • Transplantation (AREA)
  • Molecular Biology (AREA)
  • Endocrinology (AREA)
  • Hematology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to a benzo suberne type derivant with anti-HIV activity in the general formula I and medicinal salt or aqua compound thereof; definitions of substituent groups in the formula I are specified in the specification; the invention provides a preparation method for the compound in the general formula I, pharmaceutical composition containing the compound in the general formula I or the medicinal salt or aqua compound thereof and application of the compound in the general formula I or the medicinal salt or aqua compound thereof to the preparation of drugs for curing and preventing AIDS and diseases relevant to CCR5.

Description

Benzocyclohepta vinyl derivative, its preparation method and medicinal use
Technical field
The present invention relates to have the benzocyclohepta vinyl derivative of antagonizing CCR 5 activity or its pharmacologically acceptable salt, they the preparation method, comprise the pharmaceutical composition of described compound, and the purposes of the medicine of the disease that infects for the preparation for the treatment of or prevention HIV of described compound or other disease relevant with its CCR5 antagonistic action.
Background technology
Acquired immune deficiency syndrome (AIDS) (Acquired Immune Deficiency Syndrome, AIDS) is the disease that is caused by HIV.At present not only toxicity is large, complication is many for clinical anti-AIDS drugs used, and also can develop immunity to drugs in patient body, so still need to find safer, more effective approach is controlled this virus.
It is that HIV enters the required acceptor of cell that report CCR5 has been arranged, and (J Immunol, 1998,160 (8): 4018-4025.) play an important role in foundation that HIV infects with in propagating.CCR5 belongs to the cell chemotactic factor acceptor of G albumen coupling, have seven cross-film zones, be expressed in dendritic cells derived from peripheral blood, T lymphocyte, monocyte, scavenger cell and participation and remain immunocyte and the inflammatory cell of long-term inflammatory reaction, its endogenic ligand has RANTES, MIP-1 α, MIP-1 β.As CCR5 after its endogenic ligand is combined, activated G protein also causes that finally intracellular calcium concentration rises and the activation of protein kinase, show various physiological functions (J Biol Chem, 1996,271 (29): 17161-17166.) such as leukocytic chemotaxis and inflammatory reaction.
Experiment in vitro is found, thereby three kinds of endogenic ligands of CCR5 can be had a liking for scavenger cell type HIV-1 by inhibition and enter cell inhibition HIV infection, some can be combined with CCR5 and the micromolecular compound of antagonizing CCR 5 function also can be invaded cell (Bioorg Med Chem at the external HIV that very effectively suppresses, 2003,11 (13): 2663-2676).
In sum, suppressing compound that CCR5 is combined with HIV-1 or its native ligand can be for the treatment of AIDS and other and CCR5 relative disease.
Summary of the invention
The objective of the invention is to find and develop the compound with antagonizing CCR 5 activity, it can be used for treating AIDS and reaches the disease relevant with AIDS and other the disease relevant with the CCR5 antagonistic action.
The inventor has been found that the compound of general formula I as follows can be used for the treatment of or prevent the HIV infectious diseases.
Therefore, first aspect of the present invention provides compound of Formula I, its raceme or optically active isomer or its pharmacologically acceptable salt and solvate,
Figure S2008100006483D00021
Wherein:
X is-CH 2-,-O-,-NR-, R wherein is H or C 1-C 6-alkyl ,-S-, optional sulfinyl or the alkylsulfonyl of being oxidized to of described sulphur atom;
R1 is the optional C that replaces 1-C 6-alkyl; C 1-C 6-alkoxyl group; C 1-C 6Alkylthio; Optional 5～6 rings that replace;
N is 0～3 integer;
A is 5～6 rings, and this ring is optional by hydroxyl, C 1-C 6Alkyl, C 1-C 6Alkoxyl group, C 1-C 6-alkylthio, C 1-6Haloalkyl, amino, halogen, nitro or cyano group replace;
B is-CH 2-,-O-,-NR-, R wherein is H or C 1-C 10-alkyl, and the optional formation of nitrogen-atoms wherein quaternary ammonium salt ,-S-, optional sulfinyl or the alkylsulfonyl of being oxidized to of described sulphur atom;
R2 and R3 are selected from hydrogen independently of one another; The optional C that replaces 1-C 6-alkyl; Perhaps R2 forms 5～6 rings jointly with the nitrogen-atoms that R3 is connected with it, and this ring is optional by hydroxyl, C 1-C 6Alkyl, C 1-C 6Alkoxyl group, aryl, heteroaryl, C 1-C 6-alkylthio, C 1-6Haloalkyl, amino, halogen, nitro, cyano group replace.
Second aspect of the present invention relates to the preparation method of compound of Formula I or its pharmacologically acceptable salt.
Third aspect of the present invention relates to the pharmaceutical composition that contains at least a compound of Formula I or its pharmacologically acceptable salt and one or more pharmaceutical carriers or vehicle.
The 4th aspect of the present invention relates to the purposes of the medicine of disease that above-mentioned compound of Formula I or its pharmacologically acceptable salt infect for the preparation for the treatment of or prevention HIV or other disease relevant with its CCR5 antagonistic action.
The 5th aspect of the present invention relates to treats or prevents the active relevant disease of HIV and other and CCR5 or the method for illness, comprises that the object that these needs are arranged treats the compounds of this invention and all possible isomer, prodrug, pharmacologically acceptable salt, solvate or the hydrate of any one in the claim 1-3 of significant quantity.
Term " C used herein 1-C 6Alkyl ", no matter be himself or as other more macoradical such as C 1-C 6Alkoxyl group, C 1-C 6The part of alkylthio, all refer to the atomic group that contains 1-6 carbon atom of straight or branched include but are not limited to: methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-and the tertiary butyl etc.
Term " C used herein 1-C 6-alkoxyl group " refer to " C 1-C 6-alkyl-O-", the example of alkoxyl group includes but not limited to methoxyl group, oxyethyl group, isopropoxy etc.
Term " C used herein 1-C 6-alkylthio " refer to " C 1-C 6-alkyl-S-", the example of alkyl includes but not limited to methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-and the tertiary butyl etc.
Term " C used herein 1-C 6Haloalkyl " refer to the C that one or more hydrogen are wherein replaced by halogen atom 1-C 6Alkyl.
The example of term used herein " 5～6 ring " includes but not limited to 6 yuan of aromatic rings, for example benzene; 5～6 yuan of aliphatic hydrocarbons, such as pentamethylene, hexanaphthene, cyclopentenes, tetrahydrobenzene, cyclopentadiene, cyclohexadiene etc.; Contain 1～4 heteroatomic 5～6 yuan of fragrant heterocycle that are selected from Sauerstoffatom, sulphur atom and nitrogen-atoms, for example furans, thiophene, pyrroles, imidazoles, pyrazoles, thiazole,
Figure 2008100006483_0
Azoles, isothiazole, different
Figure 2008100006483_1
Azoles, tetrazolium, pyridine, pyrazine, pyrimidine, pyridazine, triazole etc.; Contain 1～4 heteroatomic 5～6 yuan of non-aromatic heterocycle that are selected from Sauerstoffatom, sulphur atom and nitrogen-atoms, for example tetrahydrofuran (THF), tetramethylene sulfide, two sulphur pentanes, oxygen sulphur pentane, tetramethyleneimine, pyrroline, imidazolidine, tetrahydroglyoxaline, pyrazolidine, give a tongue-lashing azoles quinoline, piperidines, piperazine,
Figure 2008100006483_2
Piperazine, Diazine, thiazine, thiadiazine, morpholine, thiomorpholine, pyrans, tetrahydropyrans, tetrahydric thiapyran etc.Wherein, benzene, furans, thiophene, pyridine, pentamethylene, hexanaphthene, tetramethyleneimine, piperidines, piperazine, morpholine, thiomorpholine, tetrahydropyrans are preferred.
Except the replacement that has specialized, in the term that this paper uses at all the other places " the optional replacement ", the example of " substituting group " includes but not limited to halogen, trifluoromethyl, nitro, cyano group, C 1-C 6Alkyl, hydroxyl, sulfydryl (sulphur atom wherein can be chosen wantonly and be oxidized to sulfinyl or alkylsulfonyl), amino, acyl group, esterifying carboxyl group, aryl, heteroaryl.
Term used herein " halogen (halo) " refers to fluorine (fluoro), chlorine (chloro), bromine (bromo) or iodine (iodo).
Term used herein " aryl " refers to replacement or the non-substituted aromatic ring system of 5-14 unit, maybe may comprise the dicyclo or three aromatic ring systems that encircle that condense, and includes but not limited to phenyl and naphthyl.
Term used herein " heteroaryl " refers to contain 1～4 and is selected from the heteroatomic 5-14 such as Sauerstoffatom, sulphur atom and nitrogen-atoms unit's replacement or non-substituted aromatic ring system, also may comprise the dicyclo or three aromatic ring systems that encircle that condense.
According to a preferred embodiment of the present invention, the present invention relates to compound of Formula I:
Figure S2008100006483D00041
Wherein:
X is-CH 2-,-O-;
R1 is methyl substituted phenyl;
A is the phenyl of phenyl or replacement, and substituting group is selected from methyl and methoxyl group;
B is-CH 2-,-O-
N is 0～3 integer;
R2 and R3 are selected from methyl, ethyl and sec.-propyl independently of one another; Perhaps the nitrogen-atoms that is connected with it of R2 and R 3 is common forms 5～6 rings, includes but not limited to morpholine, tetramethyleneimine, piperidines, and this ring is chosen wantonly by indole ring or by the indole ring of hydroxyl, halogen replacement and replaced.
According to the present invention one preferred embodiment, compound of Formula I of the present invention has following general formula I a:
Figure S2008100006483D00051
Wherein:
X is-CH 2-,-O-,-NR-, R wherein is H or C 1-C 6-alkyl ,-S-, described sulphur atom can be chosen wantonly and be oxidized to sulfinyl or alkylsulfonyl;
R1 is the optional C that replaces 1-C 6-alkyl; C 1-C 6-alkoxyl group; C 1-C 6Alkylthio; Optional 5～6 rings that replace;
N is 0～3 integer;
R2 and R3 are selected from hydrogen independently of one another; The optional C that replaces 1-C 6-alkyl; Perhaps R2 forms 5～6 rings jointly with the nitrogen-atoms that R3 is connected with it, and this ring is optional by hydroxyl, C 1-C 6Alkyl, C 1-C 6Alkoxyl group, aryl, heteroaryl, C 1-C 6-alkylthio, C 1-6Haloalkyl, amino, halogen, nitro, cyano group replace;
R4 is hydrogen; Halogen; Perfluoroalkyl; Carboxyl; Nitro; Cyano group; The optional C that replaces 1-C 6-alkyl, hydroxyl, C 1-C 6-alkoxyl group, sulfydryl, C 1-C 6-alkylthio (wherein sulphur atom can be chosen wantonly and be oxidized to sulfinyl or alkylsulfonyl), the optional amino that replaces, the optional acyl group that replaces, the optional esterifying carboxyl group that replaces and the optional aryl that replaces.
According to the present invention another preferred embodiment, compound of Formula I of the present invention has following general formula I b:
Figure S2008100006483D00061
Wherein:
X is-CH 2-,-O-,-NR-, R wherein is H or C 1-C 6-alkyl ,-S-, described sulphur atom can be chosen wantonly and be oxidized to sulfinyl or alkylsulfonyl;
R1 is the optional C that replaces 1-C 6-alkyl; C 1-C 6-alkoxyl group; C 1-C 6Alkylthio; Optional 5～6 rings that replace;
C is the optional phenyl ring that replaces;
D is 6 member heterocyclic ring containing nitrogens, and this ring is optional contains that one or two independently are selected from the heteroatoms of N, O and S and choose wantonly by hydroxyl, C in addition 1-C 6Alkyl, C 1-C 6Alkoxyl group, aryl, heteroaryl, C 1-C 6-alkylthio, C 1- 6Haloalkyl, amino, halogen, nitro, cyano group replace;
R7 is hydrogen; Halogen; Perfluoroalkyl; Carboxyl; Nitro; Cyano group; The optional C that replaces 1-C 6Alkyl, hydroxyl, C 1-C 6Alkoxyl group, sulfydryl, C 1-C 6Alkylthio, wherein sulphur atom can be chosen wantonly and be oxidized to sulfinyl or alkylsulfonyl, the optional amino that replaces, the optional acyl group that replaces, the optional esterifying carboxyl group that replaces and the optional aryl that replaces;
R8 is hydrogen; Halogen; Perfluoroalkyl; Carboxyl; Nitro; Cyano group; The optional C that replaces 1-C 6Alkyl, hydroxyl, C 1-C 6Alkoxyl group, sulfydryl, C 1-C 6Alkylthio, wherein sulphur atom can be chosen wantonly and be oxidized to sulfinyl or alkylsulfonyl, the optional amino that replaces, the optional acyl group that replaces, the optional esterifying carboxyl group that replaces and the optional aryl that replaces.
According to a further aspect, the invention provides the intermediate that a class can be used for preparing CCR5 antagonist as herein described.The general formula of this class intermediate is as follows:
Wherein:
X is-CH 2-,-O-,-NR-, R wherein is H or C 1-C 6-alkyl ,-S-, described sulphur atom can be chosen wantonly and be oxidized to sulfinyl or alkylsulfonyl;
R1 is the optional C that replaces 1-C 6-alkyl; C 1-C 6-alkoxyl group; C 1-C 6Alkylthio; Optional 5～6 rings that replace;
N is 0～3 integer;
R2 and R3 are selected from hydrogen independently of one another; The optional C that replaces 1-C 6-alkyl; Perhaps R2 forms 5～6 rings jointly with the nitrogen-atoms that R3 is connected with it, and this ring is optional by hydroxyl, C 1-C 6Alkyl, C 1-C 6Alkoxyl group, aryl, heteroaryl, C 1-C 6-alkylthio, C 1-6Haloalkyl, amino, halogen, nitro, cyano group replace;
R4 is hydrogen; Halogen; Perfluoroalkyl; Carboxyl; Nitro; Cyano group; The optional alkyl that replaces, hydroxyl, alkoxyl group, sulfydryl, alkylthio (wherein sulphur atom can be chosen wantonly and be oxidized to sulfinyl or alkylsulfonyl), the optional amino that replaces, the optional acyl group that replaces, the optional esterifying carboxyl group that replaces, the optional aryl that replaces etc.;
R7 is hydrogen; Halogen; Perfluoroalkyl; Carboxyl; Nitro; Cyano group; The optional C that replaces 1-C 6Alkyl, hydroxyl, C 1-C 6Alkoxyl group, sulfydryl, C 1-C 6Alkylthio, wherein sulphur atom can be chosen wantonly and be oxidized to sulfinyl or alkylsulfonyl, the optional amino that replaces, the optional acyl group that replaces, the optional esterifying carboxyl group that replaces and the optional aryl that replaces;
R8 is hydrogen; Halogen; Perfluoroalkyl; Carboxyl; Nitro; Cyano group; The optional C that replaces 1-C 6Alkyl, hydroxyl, C 1-C 6Alkoxyl group, sulfydryl, C 1-C 6Alkylthio, wherein sulphur atom can be chosen wantonly and be oxidized to sulfinyl or alkylsulfonyl, the optional amino that replaces, the optional acyl group that replaces, the optional esterifying carboxyl group that replaces and the optional aryl that replaces.
C is the optional phenyl ring that replaces;
D is 6 member heterocyclic ring containing nitrogens, and this ring is optional contains that one or two independently are selected from the heteroatoms of N, O and S and choose wantonly by hydroxyl, C in addition 1-C 6Alkyl, C 1-C 6Alkoxyl group, aryl, heteroaryl, C 1-C 6-alkylthio, C 1-6Haloalkyl, amino, halogen, nitro, cyano group replace.
The preferred compound of the present invention is selected from:
N-[3-(2-diethyl amino base oxethyl)-4-aminomethyl phenyl]-3-(4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-methane amide;
N-[3-(2-diisopropylaminoethyl oxyethyl group)-4-aminomethyl phenyl]-3-(4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-methane amide;
N-[3-(2-dimethylamino ethoxy)-4-aminomethyl phenyl]-3-(4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-methane amide;
N-[3-[2-(4-morpholinyl) oxyethyl group]-the 4-aminomethyl phenyl]-3-(4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-methane amide;
N-[3-[2-(piperidino) oxyethyl group]-the 4-aminomethyl phenyl]-3-(4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-methane amide;
The N-[3-[3-dimethylamino propoxy]-the 4-aminomethyl phenyl]-3-(4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-methane amide;
N-[3-[2-(1-pyrrolidyl) oxyethyl group]-the 4-aminomethyl phenyl]-3-(4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-methane amide;
N-[3-(2-diethyl amino base oxethyl) phenyl]-3-(4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-methane amide;
N-[3-(2-diisopropylaminoethyl oxyethyl group) phenyl]-3-(4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-methane amide;
N-[3-(2-dimethylamino ethoxy) phenyl]-3-(4-aminomethyl phenyl)-8,9-dihydro-7 H-benzo ring heptene-6-methane amide;
N-[3-[2-(4-morpholinyl) oxyethyl group] phenyl]-3-(4-aminomethyl phenyl)-8,9-dihydro-7 H-benzo ring heptene-6-methane amide;
N-[3-[2-(piperidino) oxyethyl group] phenyl]-3-(4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-methane amide;
The N-[3-[3-dimethylamino propoxy] phenyl]-3-(4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-methane amide;
N-[3-[2-(1-pyrrolidyl) oxyethyl group] phenyl]-3-(4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-methane amide;
N-[3-(2-diethyl amino base oxethyl)-4-p-methoxy-phenyl]-3-(4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-methane amide;
N-[3-(2-diisopropylaminoethyl oxyethyl group)-4-p-methoxy-phenyl]-3-(4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-methane amide;
N-[3-(2-dimethylamino ethoxy)-4-p-methoxy-phenyl]-3-(4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-methane amide;
N-[3-[2-(4-morpholinyl) oxyethyl group]-the 4-p-methoxy-phenyl]-3-(4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-methane amide;
N-[3-[2-(piperidino) oxyethyl group]-the 4-p-methoxy-phenyl]-3-(4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-methane amide;
The N-[3-[3-dimethylamino propoxy]-the 4-p-methoxy-phenyl]-3-(4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-methane amide;
N-[3-[2-(1-pyrrolidyl) oxyethyl group]-the 4-p-methoxy-phenyl]-3-(4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-methane amide;
N-[4-[4-(5-hydroxyl-3H-indol-3-yl) piperidin-1-yl methyl] phenyl]-3-(4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-methane amide;
N-[4-[4-(3H-indol-3-yl) piperidin-1-yl methyl] phenyl]-3-(4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-methane amide;
N-[3-(2-diethyl amino base oxethyl)-4-aminomethyl phenyl]-the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide;
N-[3-(2-diisopropylaminoethyl oxyethyl group)-4-aminomethyl phenyl]-the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide;
N-[3-(2-dimethylamino ethoxy)-4-aminomethyl phenyl]-the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide;
N-[3-[2-(4-morpholinyl) oxyethyl group]-the 4-aminomethyl phenyl]-the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide;
N-[3-[2-(piperidino) oxyethyl group]-the 4-aminomethyl phenyl]-the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide;
The N-[3-[3-dimethylamino propoxy]-the 4-aminomethyl phenyl]-the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide;
N-[3-[2-(1-pyrrolidyl) oxyethyl group]-the 4-aminomethyl phenyl]-the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide;
N-[3-(2-diethyl amino base oxethyl) phenyl]-the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide;
N-[3-(2-diisopropylaminoethyl oxyethyl group) phenyl]-the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide;
N-[3-(2-dimethylamino ethoxy) phenyl]-the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide;
N-[3-[2-(4-morpholinyl) oxyethyl group] phenyl]-the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide;
N-[3-[2-(piperidino) oxyethyl group] phenyl]-the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide;
The N-[3-[3-dimethylamino propoxy] phenyl]-the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide;
N-[3-[2-(1-pyrrolidyl) oxyethyl group] phenyl]-the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide;
N-[3-(2-diethyl amino base oxethyl)-4-p-methoxy-phenyl]-the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide;
N-[3-(2-diisopropylaminoethyl oxyethyl group)-4-p-methoxy-phenyl]-the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide;
N-[3-(2-dimethylamino ethoxy)-4-p-methoxy-phenyl]-the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide;
N-[3-[2-(4-morpholinyl) oxyethyl group]-the 4-p-methoxy-phenyl]-the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide;
N-[3-[2-(piperidino) oxyethyl group]-the 4-p-methoxy-phenyl]-the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide;
The N-[3-[3-dimethylamino propoxy]-the 4-p-methoxy-phenyl]-the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide;
N-[3-[2-(1-pyrrolidyl) oxyethyl group]-the 4-p-methoxy-phenyl]-the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide;
N-[4-[4-(5-hydroxyl-3H-indol-3-yl) piperidin-1-yl methyl] phenyl]-the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide;
N-[4-[4-(3H-indol-3-yl) piperidin-1-yl methyl] phenyl]-the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide;
And all possible isomer, prodrug, pharmacologically acceptable salt, solvate or hydrate.
The invention still further relates to suitable pharmaceutically useful salt, solvate or the hydrate of compound as shown in general formula I, but wherein pharmaceutically useful salt comprise the quaternary ammonium salt that is not limited to compound of Formula I or the salt that becomes with mineral acid example hydrochloric acid, sulfuric acid, phosphoric acid, phosphorous acid, Hydrogen bromide and nitric acid and with various organic acids, the salt that becomes as toxilic acid, oxysuccinic acid, fumaric acid, succsinic acid, tartrate, citric acid, acetic acid, lactic acid, methylsulfonic acid, tosic acid, palmitinic acid etc.Other acid, as oxalic acid, although itself is not pharmaceutically acceptable, can be for the preparation of the salt as intermediate, to obtain the compounds of this invention or its pharmacologically acceptable salt.
Some compounds possibility water or various organic solvent crystallization or recrystallizations in the present invention, in this case, may form various solvates.The present invention includes those stoichiometric solvates, comprise hydrate, be also included within the compound that comprises variable water gaging that forms while preparing with lyophylization.
The invention still further relates to the various isomer of compound of Formula I.In the present invention, part of compounds may exist with the form of optical isomer or tautomer, the present invention includes the form of its all existence forms, particularly pure isomer.Different isomeric forms can or split with the isomer separation of the means of various routines and other form, or the synthetic method that certain isomer can various routines or three-dimensional single-minded or method asymmetric synthesis obtain.Since compound of Formula I take medicinal as purpose, is appreciated that they preferably provide with pure form, at least 60% purity for example, more suitably 75%, better 85%, best at least 98% purity (% refers to weight percent).The preparation method of pure compound not can be used to for the purer form of pharmaceutical composition.In these pure not products, contain at least 1%, be more suitable for 5%, better at least 10% the compound as shown in general formula I or its pharmaceutically useful derivative.
On the other hand, the present invention relates to prepare the synthetic method of compound of Formula I.The compound of general formula I can be raw material from known or commercially available compound, through the method preparation of synthetic.If raw material can not be buied, this paper provides their preparation method, or they can be by the method preparation of bibliographical information.
According to the present invention, can prepare with following methods by above-mentioned compound of Formula I or its pharmacologically acceptable salt or solvate, below respectively with the subclass structrual description.
The preparation method of general formula I a compound is as follows, and wherein R1, R2, R3, R4, X, n have foregoing definition:
1) raw material 1 and the reaction of R1-alkylating reagent, the tetrahydro benzo suberene that generation R1 replaces-5-ketone (general formula 2).
A. when X is methylene radical, under the Lewis acid effect, F-K reaction occurring with bromobenzene and glutaric acid monoester acyl chlorides, generates 4-to the Brombenzyl butyric ester.Through hydrolysis, reducing carbonyl and cyclization, generate intermediate 1 again.
B. when X is oxygen, with p bromophenol, directly with the 4-bromobutanoate, under the alkali effect, react, generate 4-to bromine phenoxy group butyric ester, then through hydrolysis, reducing carbonyl and cyclization generation intermediate 1.
2) compound of the formula 2 of step-obtain is carried out to nucleophilic substitution, at ketone carbonyl ortho position, introduce methoxycarbonyl, then the reductone carbonyl is hydroxyl, then through eliminating and hydrolysis obtains the intermediate of general formula I I;
Figure S2008100006483D00122
3) starting raw material 3 and the hydrochloride of starting raw material 4 are reacted under the alkali effect, the nitro-compound of generation, through reduction, obtains the intermediate of general formula III.
Figure S2008100006483D00131
4) the intermediate II carboxyl is converted into to acyl chlorides, then reacts with intermediate III, obtain the Ia compounds.
The building-up reactions scheme of general formula I a compound refers to following reaction scheme, and wherein R1, R2, R3, R4, X, n have definition as above:
Reactions steps one:
Figure S2008100006483D00132
A. when X is methylene radical
Bromobenzene and aluminum chloride are placed in to three-necked bottle, under ice bath, slowly drip the monomethyl glutarate acyl chlorides, dropwise rear room temperature reaction 2～4 hours.Reaction mixture is poured in the mixture of hydrochloric acid and ice, separate organic phase, the water ethyl acetate extraction, merge organic phase, washing, the saturated common salt washing, anhydrous sodium sulfate drying, filter, decompression steams bromobenzene, the yellow oil that obtains is dissolved in tetrahydrofuran (THF), then adds water and lithium hydroxide solution, stirring at room 1～3 hour.Be spin-dried for tetrahydrofuran (THF), add the water dilution, use the ethyl acetate extraction water, organic phase discards.The aqueous solution is regulated pH value to acid with hydrochloric acid, uses dichloromethane extraction, combining extraction liquid, washing; the saturated common salt washing, anhydrous sodium sulfate drying, filter, and is spin-dried for; the white solid that obtains is dissolved in trifluoroacetic acid, under nitrogen protection, drips triethyl silicane, reacts 40～60 hours under 30～70 ℃.Reaction is spin-dried for solvent, and the solid that obtains dissolves with sodium hydroxide solution, with ether, washes, and discards organic phase.The water hcl acidifying, use the ethyl acetate extraction water.Merge organic phase, washing, the saturated common salt washing, anhydrous sodium sulfate drying, be spin-dried for, and the ether recrystallization obtains white solid 9.
B. when X is Sauerstoffatom
P bromophenol and 4-bromo-butyric acid ethyl ester are dissolved in to DMF, stirred overnight at room temperature under the salt of wormwood effect.Reaction mixture is poured in ice, used ethyl acetate extraction, merge organic phase, washing, the saturated common salt washing, anhydrous sodium sulfate drying, be spin-dried for, and the oily matter that obtains is dissolved in methyl alcohol, then adds sodium hydroxide solution, refluxes half an hour.Be spin-dried for methyl alcohol, the products therefrom water dissolution, wash with ether, discards organic phase.Use again the hcl acidifying obtained aqueous solution, then use ethyl acetate extraction, merge organic phase, washing, the saturated common salt washing, anhydrous sodium sulfate drying, obtain white solid 9.In this law, the represented Sauerstoffatom of X can be replaced with sulphur atom.
Reactions steps two:
Figure S2008100006483D00141
White solid 9 is mixed with polyphosphoric acid, and 80～120 ℃ were heated 10～16 hours.Reaction solution is poured in mixture of ice and water, uses ethyl acetate extraction, merges organic phase.(eluent: the petrol ether/ethyl acetate system), obtain yellow oil 1, by 1, with the R1-phenylo boric acid, mix, add ethanol, wet chemical, toluene, under nitrogen protection, stirring at room is 20～60 minutes in concentrated rear pillar separation.In reaction system, add four (triphenylphosphine palladium) catalysis, nitrogen protection refluxes and spends the night.The product separation organic phase, the water ethyl acetate extraction, merge organic phase, and concentrated rear pillar separates (eluent: the petrol ether/ethyl acetate system), obtain white solid 2.
Reactions steps three:
Methylcarbonate, sodium hydride are mixed with anhydrous dioxane, after reflux, be added dropwise to 2 anhydrous dioxane solution, refluxed two hours.With the hydrochloric acid neutralization, separate organic phase, the water ethyl acetate extraction, merge organic phase, washing, the saturated common salt washing, anhydrous sodium sulfate drying, be spin-dried for.The white solid that obtains is dissolved in the mixed solvent of tetrahydrofuran (THF) and water, adds sodium borohydride under-8～-20 ℃, and under nitrogen protection ,-5～-10 ℃ of stirrings are spent the night.Add after completion of the reaction water and ethyl acetate, separate organic phase, the water ethyl acetate extraction, merge organic phase, and concentrated rear pillar separates (eluent: the petrol ether/ethyl acetate system), obtain white solid 10.Reactions steps four (can independently be realized by following a and two kinds of methods of b respectively):
A. by 10 mixed solvents that are dissolved in methyl alcohol and ether, add sodium hydroxide solution, stirring at room half an hour.Reaction mixture is spin-dried for, adds water dissolution, use the ether extraction water, organic phase discards.Use the hcl acidifying water, ethyl acetate extraction, merge organic phase, washing, the saturated common salt washing, anhydrous sodium sulfate drying, be spin-dried for filtration, the white solid that obtains is dissolved in hydrochloric acid and diglyme, 80～120 ℃ were heated 30～60 minutes, screwed out most of solvent, and remaining liq is poured in mixture of ice and water, filter, obtain intermediate II.
B. by 10, be dissolved in anhydrous tetrahydro furan, add triethylamine and be cooled to 5～-5 ℃, be added dropwise to methylsulfonyl chloride, room temperature reaction 3～8 hours.Add DBU, room temperature reaction spends the night again.In reaction system, add water and ethyl acetate, separate and use the ethyl acetate extraction water, merge organic phase, washing, saturated common salt washing, anhydrous sodium sulfate drying, filtration is spin-dried for and obtains the mixed solvent that product is dissolved in methyl alcohol and tetrahydrofuran (THF), adds sodium hydroxide solution, stirred overnight at room temperature.Reaction mixture is spin-dried for, adds water dissolution, use the ether extraction water, organic phase discards.Use the hcl acidifying water, ethyl acetate extraction, merge organic phase, washing, and the saturated common salt washing, anhydrous sodium sulfate drying, be spin-dried for filtration, obtains intermediate II.
Reactions steps five:
Figure S2008100006483D00152
In the mixed solvent of starting raw material 3 and salt of wormwood is water-soluble and acetone, add the hydrochloride of raw material 4, refluxed 8～16 hours.After reaction mixture is concentrated, uses hcl acidifying, and wash with ethyl acetate, organic phase discards.Water alkalizes with saturated solution of potassium carbonate, then uses ethyl acetate extraction, merges organic phase, and concentrated rear pillar separates (eluent: the methylene chloride/methanol system), obtain yellow oil 11.Be dissolved in ethanol by 11, add palladium carbon, under 40～60 ℃, drip hydrazine hydrate, refluxed 20 minutes to 1 hour, cold filtration palladium carbon, the concentrated intermediate III that obtains.
Reactions steps six:
Figure S2008100006483D00161
Intermediate II is dissolved in to anhydrous tetrahydro furan; add catalytic amount DMF; under ice bath, drip oxalyl chloride; stirring at room 1.5～3 hours; after being spin-dried for, reaction solution is dissolved in anhydrous tetrahydro furan; under ice bath, be added drop-wise in the anhydrous tetrahydrofuran solution of intermediate III and triethylamine, under nitrogen protection, room temperature reaction spends the night.Add water and ethyl acetate, separate organic phase, use the ethyl acetate extraction water, merge organic phase, concentrated rear pillar separates (eluent: the methylene chloride/methanol system), obtain Compound I a.
The preparation method of general formula I b compounds is as follows, wherein R1, R7, R8, X, C, D, have foregoing definition:
1) described in the synthetic method of intermediate II such as front Ia compounds.
2) starting raw material 5 and raw material 6 are generated under the alkali effect in the middle of 7, through reduction, again with to after the nitrobenzyl bromine reaction, obtain intermediate 8, the nitro that reduces obtains intermediate compound IV.
Figure S2008100006483D00162
3) carboxyl of intermediate II is converted into to acyl chlorides, then reacts with intermediate compound IV, obtain the Ib compounds.R7 in mutual-through type Ib compound and R8 can carry out functional group's conversion according to methods known in the art.
The building-up reactions scheme of general formula I b compounds refers to following reaction scheme, and wherein step-to step 4 is with the building-up reactions route of aforementioned Ia compounds intermediate II, R1, R7, R8, X, C, D, has foregoing definition:
Reactions steps five:
Figure S2008100006483D00171
By starting raw material 5 and methanol mixed, add sodium methoxide solution, then add reactant 6, refluxed 12～20 hours.Reaction solution is cooling rear with methylene dichloride and methyl alcohol dilution, and regulates below pH value to 5 with Glacial acetic acid, and concentration of reaction solution, add water, and use ethyl acetate extraction.Merge organic phase, washing, the saturated common salt washing, anhydrous sodium sulfate drying, be spin-dried for, and the solid that obtains and palladium carbon are put into methyl alcohol, under nitrogen protection-and inferior property adds the anhydrous formic acid ammonium, and reflux, filter, and is spin-dried for, and obtains intermediate 12.
Reactions steps six:
By intermediate 12, nitrobenzyl bromine, triethylamine are dissolved in acetone, refluxed 40～80 minutes.In cooled reaction solution, add water and ethyl acetate, separate organic phase, the water ethyl acetate extraction, merge organic phase, concentrated rear pillar separates (eluent: sherwood oil/acetone system), the intermediate 8 that obtains is dissolved in tetrahydrofuran (THF), drips the concentrated hydrochloric acid solution of tindichloride, stirring at room 40～80 minutes.In reaction system, add tetrahydrofuran (THF) and water, then alkalize with sodium hydroxide solution.Separate organic phase, water extracts with tetrahydrofuran (THF), merges organic phase, and concentrated rear pillar separates (eluent: the methylene chloride/methanol system), obtain intermediate compound IV.
Reactions steps seven:
Figure S2008100006483D00181
Intermediate II is dissolved in to anhydrous tetrahydro furan; add catalytic amount DMF; under ice bath, drip oxalyl chloride; stirring at room 1.5～3 hours; after being spin-dried for, reaction solution is dissolved in anhydrous tetrahydro furan; under ice bath, be added drop-wise in the anhydrous tetrahydrofuran solution of intermediate III and triethylamine, under nitrogen protection, room temperature reaction spends the night.Add water and ethyl acetate, separate organic phase, use the ethyl acetate extraction water, merge organic phase, concentrated rear pillar separates (eluent: the methylene chloride/methanol system), obtain compounds ib.R5 in mutual-through type Ib compound and R6 can carry out functional group's conversion according to methods known in the art.
Compound of Formula I can be single synthetic with ordinary method, also the available combination chemistry mixed-separating method or parallel synthetic method (contain two at least with storehouse in each storehouse, or 5-1000,10-100 compound preferably) synthetic for unit, namely can in liquid phase, synthesize also and can use solid phase synthesis process.
About the more detailed information of preparation compound of Formula I, see embodiment.
The present invention also comprises the prodrug of the compounds of this invention, and this prodrug, once administration, namely carries out chemical conversion by metabolic process, becomes afterwards the activated medicine of tool.Usually, this class prodrug is the functional derivatives of the compounds of this invention, and it easily changes into the compound of required formula (I) in vivo.For example, at " Design Of Prodrugs ", H Bund Saard, Elsevier edits, and has described the ordinary method of selecting and prepare suitable prodrug derivant in 1985.
The present invention also comprises the active metabolite of the compounds of this invention.
It will be appreciated by those skilled in the art that the compounds of this invention also can use with the form of its pharmacologically acceptable salt or solvate.The pharmacologically acceptable salt of formula I compound comprises the salt of the routine that forms with pharmaceutically acceptable mineral acid or organic acid or mineral alkali or organic bases and the acid salt of quaternary ammonium.
On the other hand, the present invention relates to compound, its all possible isomer, prodrug, pharmacologically acceptable salt, solvate or the hydrate of the general formula I purposes for the production of medicine, described medicine is used for the treatment of and prevents the mammiferous disease relevant to the CCR5 activity.Described disease is including, but not limited to following disease: AIDS, sacroiliitis, rheumatoid arthritis, inflammatory bowel, atopic dermatitis, psoriasis, asthma, multiple sclerosis, solid organ transplantation repulsion, graft versus host disease (GVH disease), Alzheimer, local anaphylaxis, arteriosclerosis, meat shape knurl disease, chronic obstructive pulmonary disease, ephritis (ephrosis), diabetes, sarcoidosis, fibrosis, atherosclerosis etc.
On the other hand; the compound of general formula I of the present invention or its pharmaceutically useful salt can use separately; or the form with pharmaceutical composition is used together with pharmaceutically useful carrier or vehicle; when the form with pharmaceutical composition is used; usually by the compound of Formula I of the present invention of effective dose or its pharmacologically acceptable salt or hydrate and one or more pharmaceutically acceptable carrier or thinner in conjunction with making suitable administration form or dosage form, this program comprises by suitable mode component mixing, granulation, compression or dissolving.Therefore, the invention provides pharmaceutical composition, it comprises compound, its all possible isomer, prodrug, pharmacologically acceptable salt, solvate or hydrate and at least a pharmaceutically useful carrier of general formula I.
Described pharmaceutical carrier includes but not limited to: ion-exchanger, aluminum oxide, aluminum stearate, Yelkin TTS, serum protein such as human serum albumin, buffer substance such as phosphoric acid salt, glycerine, Sorbic Acid, potassium sorbate, the partial glycerol ester mixture of saturated vegetable fatty acid, water, salt or ionogen, as protamine sulfate, Sodium phosphate dibasic, potassium hydrogen phosphate, sodium-chlor, zinc salt, colloided silica, Magnesium Trisilicate, polyvinylpyrrolidone, cellulosic material, polyoxyethylene glycol, Xylo-Mucine, polyacrylic ester, beeswax, lanolin.The content of carrier in pharmaceutical composition can be 1 % by weight-98 % by weight, usually accounts for greatly 80 % by weight.For simplicity, local anesthetic, sanitas, buffer reagents etc. can directly be dissolved in carrier.
The pharmaceutical composition of the compounds of this invention, optional approach that can following aspect is granted: in oral, spraying suction, rectal administration, intranasal administration, vagina administration, topical, parenterai administration such as subcutaneous, vein, intramuscular, intraperitoneal, sheath, in ventricle, in breastbone or intracranial injection or input, or by a kind of reservoir medication of outer planting, wherein preferred oral, intramuscular injection, intraperitoneal or intravenously application method.
Pharmaceutical composition of the present invention comprises formula I compound or pharmaceutically acceptable salt thereof of the present invention or hydrate and one or more suitable pharmaceutically acceptable carrier of effective dose.It can be used for interior therapeutic and has biocompatibility.Described pharmaceutical composition can be prepared into according to the needs of different way of administration various formulations.
The compounds of this invention can the medication of aseptic injection preparation form, comprises aseptic injection water or oil suspension or aseptic injectable solution.Wherein, spendable carrier and solvent comprise water, Ringer's solution and isotonic sodium chlorrde solution.In addition, sterilizing fixed oil also can be used as solvent or suspension medium, as direactive glyceride or two glyceryl ester.
The compounds of this invention or contain its pharmaceutical composition can the unit dosage form administration.Form of administration can be liquid dosage form, solid dosage.Liquid dosage form can be true solution class, colloidal type, particulate formulations, emulsion dosage form, mixed suspension form.Other formulations such as tablet, capsule, dripping pill, aerosol, pill, pulvis, solution, suspensoid, emulsion, granule, suppository, lyophilized injectable powder, inclusion compound, implants, patch, liniment etc.
Oral tablet and capsule can contain vehicle such as tackiness agent, as syrup, and gum arabic, sorbyl alcohol, tragacanth, or polyvinylpyrrolidone, weighting agent, as lactose, sucrose, W-Gum, calcium phosphate, sorbyl alcohol, Padil, lubricant, as Magnesium Stearate, talcum, polyoxyethylene glycol, tripoli, disintegrating agent, as yam starch, or acceptable dibutyl phthalate, as bay sodium alkoxide vitriol.Tablet can be with known method dressing on pharmacopedics.
Oral liquid can be made the suspension of water and oil, solution, and emulsion, syrup or elixir, also can make dry product, with front make up water or other suitable medium.This liquid preparation can comprise conventional additive, as suspension agent, and sorbyl alcohol, Walsroder MC 20000S, dextrose syrup, gel, Natvosol, carboxymethyl cellulose, aluminium stearate gel, the food oils of hydrogenation, emulsifying agent, as Yelkin TTS, sorb gathers candy list oleate, Sudan Gum-arabic; Or nonaqueous carrier (may comprise edible oil), as Prunus amygdalus oil, grease such as glycerine, ethylene glycol, or ethanol; Sanitas, as methyl p-hydroxybenzoate or propyl ester, Sorbic Acid.As needs, can add seasonings or tinting material.
Suppository can comprise conventional suppository base, as cocoa butter or other glyceryl ester.
Stomach is offerd medicine outward, and liquid formulation is made by the carrier of compound and a kind of sterilization usually.The first-selected water of carrier.According to the difference of selected carrier and drug level, compound had both dissolved in carrier and also can be made into aaerosol solution, and was first that compound is soluble in water when making injection solution, in after filter-sterilized, pack into sealed bottle or ampoule.
When topical application, the compounds of this invention can be made suitable ointment, lotion, or the form of creme, and wherein activeconstituents suspends or is dissolved in one or more carrier.Wherein the operable carrier of ointment formulation is including, but not limited to mineral oil, Albolene, white vaseline, propylene glycol, polyoxyethylene, polyoxytrimethylene, emulsifying wax and water; The spendable carrier of lotion and creme includes but not limited to: mineral oil, and sorbitan monostearate, polysorbate60, the n-Hexadecane ester type waxes, cetene is fragrant and mellow, 2-Standamul G, benzyl alcohol and water.
According to the difference of administering mode, in component, can contain weight ratio 0.1%, or the active ingredient of weight ratio 10-60% more suitably.But while in component, comprising unitary dose, each unit preferably comprises 50-500 milligram activeconstituents.
Must recognize, the best dosage of compound of Formula I and interval are to determine by compound property with such as form, path and the position of administration and the external conditionss such as specific Mammals for the treatment of, and this best dosage can be determined with conventional technology.Also must recognize simultaneously, the best course for the treatment of, i.e. the dosage of compound of Formula I every day within the specified time, available method well known in the art is determined.
It may be noted that in addition, using dosage and the using method of the compounds of this invention depend on factors, comprise patient's age, body weight, sex, natural health situation, nutritional status, activity intensity, Time of Administration, metabolic rate, the severity of illness and diagnosis and treatment doctor's the subjective judgement of compound.Preferred using dosage is between 0.01～100mg/kg body weight/day, and wherein optimal dosage is in the 5mg/kg-10mg/kg body weight/day.
Embodiment
Following embodiment will further illustrate the present invention, but these embodiment do not form any limitation of the invention.
The fusing point of compound is measured by the RY-1 melting point apparatus, and thermometer is calibration not.Compound 1H-NMR spectrum is measured by Bruker ARX 400 type nuclear magnetic resonance spectrometers.The FAB mass spectrum is measured by Zabspect high resolution magnetic mass spectrometer (resolving power 1000).
Embodiment 1:N-[3-(2-diethyl amino base oxethyl)-4-aminomethyl phenyl]-3-(4-aminomethyl phenyl)-8, the preparation of 9-dihydro-7H-benzo ring heptene-6-methane amide
Figure S2008100006483D00221
A. 4-(4-benzoyl bromide) methyl-butyrate
Bromobenzene (150ml) and aluminum chloride (0.3mol) are placed in to the 250ml three-necked bottle, under ice bath, slowly drip monomethyl glutarate acyl chlorides (0.14mol), room temperature reaction 3.5 hours, pour into reaction mixture in the mixture of hydrochloric acid and ice, separates organic phase.The water ethyl acetate extraction, merge organic phase, water and saturated common salt washing.Anhydrous magnesium sulfate drying, filter, and the most of bromobenzene of pressure reducing and steaming, obtain yellow oil 39.1g, yield 98%.Purifying, be not directly used in next step reaction.
B. 4-(4-benzoyl bromide) butyric acid
The yellow oil (0.12mol) that top step a is obtained is placed in the 2000ml round-bottomed flask, adds the lithium hydroxide solution (200ml) of 1mol/L, water (200ml), tetrahydrofuran (THF) (500ml), stirring at room 1.5 hours.Be spin-dried for tetrahydrofuran (THF), add the dilution of 500ml water, use the ethyl acetate extraction water, organic phase discards.With 1mol/L hydrochloric acid, regulate below pH value to 5, use dichloromethane extraction, combining extraction liquid, water and saturated common salt washing.Anhydrous magnesium sulfate drying, filter, and is spin-dried for, and obtains white solid 28.3g, yield 87%.mp 99-101℃。 1H-NMR(DMSO-d 6，400MHz)：δ1.78-1.85(2H，m)，2.28-2.32(2H，m)，3.03-3.10(2H，m)，7.72-7.76(2H，m)，7.87-7.91(2H，m)，12.51(1H，s)。
C. 4-bromobenzene valeric acid
White solid (0.06mol) prepared by the top described method of step b is dissolved in trifluoroacetic acid (32.4m1); under nitrogen protection, drip triethyl silicane (0.15mol); under 55 ℃, reaction is 48 hours; be spin-dried for solvent; obtaining solid dissolves with the 1mol/L sodium hydroxide solution; with ether, wash, organic phase discards.Water 1mol/L hcl acidifying, use the ethyl acetate extraction water, merges organic phase, water and saturated common salt washing, and anhydrous magnesium sulfate drying, be spin-dried for, and available ether recrystallization is once if necessary.Obtain white solid 11.4g.Yield 74%.mp 90-93℃。1H-NMR(CDCl3，400MHz)：δ1.62-1.69(4H，m)，2.34-2.41(2H，m)，2.55-2.62(2H，m)，7.05(2H，d，J＝8.4Hz)，7.40(2H，d，J＝8.4Hz)。
D. 3-is bromo-6,7,8,9-tetrahydrochysene-5H-benzo ring heptene-5-ketone
White solid (0.033mol) prepared by the top described method of step c is placed in the 500ml round-bottomed flask with polyphosphoric acid 200g, and 100 ℃ were heated 12 hours.Reaction solution is poured in mixture of ice and water, and the water ethyl acetate extraction merges organic phase.Organic phase is used the 1mol/L sodium hydroxide solution successively, water, and the saturated common salt washing, anhydrous magnesium sulfate drying, be spin-dried for.The product post separates (eluent: the petrol ether/ethyl acetate system), obtain yellow oil 5.3g.Yield 67%. 1H-NMR(CDCl 3，400MHz)：δ1.81-1.87(4H，m)，2.71-2.73(2H，m)，2.74-2.88(2H，m)，7.08(1H，d，J＝8.1Hz)，7.52(1H，dd，J＝2.2，8.1Hz)，7.84(1H，d，J＝2.2Hz)。
E. 3-(4-aminomethyl phenyl)-6,7,8,9-tetrahydrochysene-5H-benzo ring heptene-5-ketone
The yellow oil (0.016mol) that the top steps d is obtained is placed in the 250ml three-necked bottle with 4-methylphenylboronic acid (0.018mol), adds ethanol (26ml), 2mol/L wet chemical (26ml), toluene (80ml).Under the room temperature nitrogen protection, stir after 30 minutes, add tetrakis triphenylphosphine palladium (0.63mmol), nitrogen protection refluxes and spends the night.Separate organic phase, the water layer ethyl acetate extraction, merge organic phase, water and saturated common salt washing, and anhydrous magnesium sulfate drying, be spin-dried for, and the product post separates (eluent: the petrol ether/ethyl acetate system), obtain white solid 3.9g, yield 98%.mp 62-64℃。 1H-NMR(CDCl 3，400MHz)：δ1.85-1.91(4H，m)，2.39(3H，s)，2.76(2H，m)，2.95(2H，m)，7.23-7.25(3H，m)，7.50(2H，d，J＝8.0Hz)，7.63(1H，dd，J＝2.0，8.0Hz)，7.96(1H，d，J＝2.0Hz)。
F. 3-(4-aminomethyl phenyl)-6,7,8,9-tetrahydrochysene-5H-benzo ring heptene-5-ketone-6-formic acid Methyl esters
Methylcarbonate (0.03mol) and 60% sodium hydride (0.03mol) are placed in to the 100ml three-necked bottle, add dry anhydrous dioxane (27ml).After reflux, the white solid (0.015mol) that top step e is obtained is dissolved in anhydrous dioxane (4ml), under nitrogen protection, drips in three-necked bottle, refluxes two hours.With the neutralization of 4mol/L hydrochloric acid, separate organic phase, the water ethyl acetate extraction, merge organic phase, water and saturated common salt washing, anhydrous magnesium sulfate drying, be spin-dried for, product can, with the mixed solvent recrystallization of acetone and sherwood oil, obtain white solid 4.4g, yield 96%.mp 73-74℃。1H-NMR(CDCl3，400MHz)：δ2.04-2.17(4H，m)，2.39(3H，s)，2.66(2H，m)，2.98(1H，m)，3.85(3H，s)，7.24-7.26(3H，m)，7.49-7.85(4H，m)。
G. 3-(4-aminomethyl phenyl)-5-hydroxyl-6,7,8,9-tetrahydrochysene-5H-benzo ring heptene-6-first The acid methyl esters
The white solid (0.013mol) that top step f is obtained is dissolved in the mixed solvent of tetrahydrofuran (THF) (20ml) and water (2ml);-15 ℃ add sodium borohydride (0.84g; 0.022mol), under nitrogen protection ,-15 ℃～-5 ℃ stirrings are spent the night.Add water and ethyl acetate, separate organic phase, the water ethyl acetate extraction, merge organic phase, uses successively 1mol/L hydrochloric acid, water, and the saturated common salt washing, anhydrous magnesium sulfate drying, be spin-dried for.Obtain white solid 3.7g, yield 91%.mp104-107℃。1H-NMR(CDCl3，400MHz)：δ1.98-2.04(4H，m)，2.38(3H，s)，2.69-2.83(3H，m)，3.02-3.25(1H，m)，3.74(3H，s)，7.12-7.24(3H，m)，7.37-7.87(4H，m)。
H. 3-(4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-methyl-formiate
The white solid (7.7mmol) that the top step g is obtained is dissolved in anhydrous tetrahydro furan (27ml), adds triethylamine (23.1mmol), is cooled to 0 ℃, drips methylsulfonyl chloride (11.6mmol), room temperature reaction 6 hours.In reaction solution, add DBU (9mmol), room temperature reaction spends the night.In reaction mixture, add water and ethyl acetate, separate organic phase, the water ethyl acetate extraction, merge organic phase, water and saturated common salt washing.Anhydrous magnesium sulfate drying, filter, and is spin-dried for, and the product post separates (eluent: the petrol ether/ethyl acetate system), obtain white solid 2.2g, yield 97%.mp 126-127℃。1H-NMR(DMSO-d6，400MHz)：δ1.95-2.02(4H，m)，2.33(3H，s)，2.62-2.80(2H，m)，3.61-3.99(1H，m)，4.86-5.12(1H，m)，5.44-5.73(1H，br)，7.14-7.23(3H，m)，7.47-7.88(4H，m)，12.51(1H，s)。
I. 3-(4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-formic acid
The white solid (7.32mmol) that top step h is obtained is placed in the 250ml round-bottomed flask, adds 1N sodium hydroxide solution (40ml), methyl alcohol (20ml), tetrahydrofuran (THF) (40ml), stirred overnight at room temperature.Reaction solution is spin-dried for, and adds water to dilute and uses the 1N hcl acidifying, uses ethyl acetate extraction, and water discards, merge organic phase, water and saturated common salt washing, anhydrous magnesium sulfate drying, filter, be spin-dried for, resulting product, with ethyl acetate and sherwood oil recrystallization, obtains white solid 1.8g, yield 89%.mp 184-187℃。 1H-NMR(DMSO-d 6，400MHz)：δ1.92-1.98(2H，m)，2.34(3H，s)，2.56(2H，m)，2.80-2.82(2H，m)，7.25-7.28(3H，m)，7.50-7.72(5H，m)，12.51(1H，s)。
J. Diethyl-[2-(2-methyl-5-nitro phenoxy group) ethyl] amine
By starting raw material 2-methyl-5-nitro phenol (0.0048mol) with after salt of wormwood (0.01mol) mixes, be dissolved in the mixed solvent of acetone (33.3ml) and water (10ml), add N, N-diethyl ethylamine hydrochloride, (0.01mol), reflux is 10 hours.Reaction mixture is concentrated, use the 2mol/L hcl acidifying, gained solution is washed with ethyl acetate, discards organic phase.Water, with the alkalization of unsaturated carbonate potassium solution, is used ethyl acetate extraction, anhydrous sodium sulfate drying, and filtration is spin-dried for, and the products therefrom evaporating column separates (eluent: the methylene chloride/methanol system), obtain yellow oil 1 gram.Yield 70%.MS[M]+＝252.3m/e。
K. 3-(2-diethylin oxyethyl group)-4-monomethylaniline
The yellow oil (0.9mmol) that obtains in the step j of top is dissolved in to ethanol (12ml), adds 10% palladium carbon (0.03g), heating, add 85% hydrazine hydrate (3.6mmol) below 60 ℃, reflux half an hour.Reaction solution is cooling, diatomite filtration, and gained filtrate is spin-dried for, and obtains colorless oil 0.19g, productive rate 95%.MS[M]+＝222.3m/e。
1. N-[3-(2-diethyl amino base oxethyl)-4-aminomethyl phenyl]-3-(4-methylbenzene Base)-8,9-dihydro-7H-benzo ring heptene-6-methane amide
The white solid (0.48mmol) that the top step I is obtained is dissolved in anhydrous tetrahydro furan (2ml), adds the DMF of catalytic amount, under ice bath, slowly drips oxalyl chloride (1.44mmol), dropwises rear stirring at room two hours.Be spin-dried for reaction solution, product is dissolved in anhydrous tetrahydro furan (2ml), under ice bath, is added drop-wise in the anhydrous tetrahydrofuran solution of oily matter (0.53mmol) that step k obtains and triethylamine (1.65mmol), and under nitrogen protection, room temperature reaction spends the night.React complete water and the ethyl acetate of adding, separate organic phase, the water ethyl acetate extraction, merge organic phase.Concentrated rear pillar separates (eluent: methylene dichloride/sherwood oil system), obtain title compound, be faint yellow solid.1H-NMR(400MHz，DMSO-d 6)δppm：1.23(t，6H)，1.97-2.00(m，2H)，2.11(s，3H)，2.30(s，3H)，2.58(t，2H)，2.78-2.81(m，2H)，3.20(m，4H)，3.52(m，2H)，4.27(br，2H)，7.06-7.64(m，11H)，10.00(s，1H)；FAB-MS(m/z)：483.3[M+H]+。
Embodiment 2:N-[3-(2-diisopropylaminoethyl oxyethyl group)-4-aminomethyl phenyl]-3-(4-aminomethyl phenyl)-8, the preparation of 9-dihydro-7H-benzo ring heptene-6-methane amide
Figure S2008100006483D00261
A. Di-isopropyl-[2-(2-methyl-5-nitro phenoxy group) ethyl] amine
Adopt the method for preparing diethyl-[2-(2-methyl-5-nitro phenoxy group) ethyl] amine in embodiment 1, by the N in embodiment 1 step j, N-diethyl ethylamine hydrochloride is replaced with the DIPEA hydrochloride, obtains yellow oil.MS[M]+＝280.4m/e。
B. 3-(2-Diisopropylamine base oxethyl)-4-methyl base amine
Adopt the method for preparing 3-(2-diethylin oxyethyl group)-4-monomethylaniline in embodiment 1, di-isopropyl that diethyl in embodiment 1 step k-[2-(2-methyl-5-nitro phenoxy group) ethyl] amine obtains with top step a-[2-(2-methyl-5-nitro phenoxy group) ethyl] amine is replaced, obtained colorless oil.MS[M]+＝250.4m/e。
C. N-[3-(2-diisopropyl ammonia base oxethyl)-4-aminomethyl phenyl]-3-(4-methylbenzene Base)-8,9-dihydro-7H-benzo ring heptene-6-methane amide
Adopt the preparation method of step 1 in embodiment 1, the 3-in step 1 (2-diethylamide base oxethyl)-4-monomethylaniline is replaced with the 3-that obtains in the step b of top (2-Diisopropylamine base oxethyl)-4-monomethylaniline, obtain title compound.1H-NMR(400MHz，CDCl 3)δppm：1.04-1.06(d，12H)，2.13-2.20(m，5H)，2.39(s，3H)，2.68-2.72(t，2H)，2.85-2.89(m，4H)，3.06-3.10(m，2H)，3.92-3.96(t，2H)，6.91-7.52(m，11H)，7.65(br，1H)；FAB-MS(m/z)：511.4[M+H]+。
Embodiment 3:N-[3-(2-dimethylamino ethoxy)-4-aminomethyl phenyl]-3-(4-aminomethyl phenyl)-8, the preparation of 9-dihydro-7H-benzo ring heptene-6-methane amide
Figure S2008100006483D00271
A. Dimethyl-[2-(2-methyl-5-nitro phenoxy group) ethyl] amine
Adopt the method for preparing diethyl-[2-(2-methyl-5-nitro phenoxy group) ethyl] amine in embodiment 1, by the N in embodiment 1 step j, N-diethyl ethylamine hydrochloride N, N-dimethyl amine hydrochloride is replaced, and obtains yellow oil.MS[M]+＝224.3m/e
B. 3-(2-dimethylamino ethoxy)-4-monomethylaniline
Adopt the method for preparing 3-(2-diethylin oxyethyl group)-4-monomethylaniline in embodiment 1, dimethyl that diethyl in embodiment 1 step k-[2-(2-methyl-5-nitro phenoxy group) ethyl] amine obtains with top step a-[2-(2-methyl-5-nitro phenoxy group) ethyl] amine is replaced, obtained colorless oil.MS[M]+＝194.3m/e
C. N-[3-(2-dimethyl oxyethyl group)-4-aminomethyl phenyl]-3-(4-aminomethyl phenyl)-8,9- Dihydro-7H-benzo ring heptene-6-methane amide
Adopt the preparation method of step 1 in embodiment 1, the 3-in step 1 (2-diethylamide base oxethyl)-4-monomethylaniline is replaced with the 3-that obtains in the step b of top (2-dimethylamino ethoxy)-4-monomethylaniline, obtain title compound.1H-NMR(400MHz，CDCl 3)δppm：2.13-2.20(m，5H)，2.38-2.40(d，9H)，2.68-2.72(t，2H)，2.79-2.83(t，2H)，2.86-2.89(t，2H)，4.11-4.15(t，2H)，6.87-7.52(m，11H)，7.70(br，1H)；FAB-MS(m/z)：455.3[M+H]+。
Embodiment 4:N-[3-[2-(4-morpholinyl) oxyethyl group]-the 4-aminomethyl phenyl]-3-(4-aminomethyl phenyl)-8, the preparation of 9-dihydro-7H-benzo ring heptene-6-methane amide
Figure S2008100006483D00272
A. 4-[2-(2-methyl-5-nitro phenoxy group) ethyl] morpholine
Adopt the method for preparing diethyl-[2-(2-methyl-5-nitro phenoxy group) ethyl] amine in embodiment 1, by the N in embodiment 1 step j, N-diethyl ethylamine hydrochloride is replaced with 4-(2-chloroethyl) morpholine hydrochloride, obtains yellow solid.MS[M]+＝266.3m/e。
B. 4-methyl-3-[2-(4-morpholinyl) oxyethyl group] aniline
Adopt the method for preparing 3-(2-diethylin oxyethyl group)-4-monomethylaniline in embodiment 1, by 4-[2-(the 2-methyl-5-nitro phenoxy group) ethyl that the diethyl in embodiment 1 step k-[2-(2-methyl-5-nitro phenoxy group) ethyl] amine obtains with top step a] the morpholine replacement, obtain colorless oil.MS[M]+＝236.3m/e。
C. N-[3-[2-(4-morpholinyl) oxyethyl group]-the 4-aminomethyl phenyl]-3-(4-methylbenzene Base)-8,9-dihydro-7H-benzo ring heptene-6-methane amide
Adopt the preparation method of step 1 in embodiment 1, by the 3-in step 1 (2-diethylamide base oxethyl)-4-monomethylaniline with the 4-methyl-3-[2-that obtains in the step b of top (4-morpholinyl) oxyethyl group] the aniline replacement, obtain title compound.1H-NMR(400MHz，CDCl 3)δppm：2.14-2.19(m，5H)，2.40(s，3H)，2.67-2.73(m，6H)，2.86-2.90(m，4H)，3.77(m，4H)，4.19-4.22(t，2H)，6.84-7.52(m，11H)，7.64(br，1H)；FAB-MS(m/z)：4 97.3[M+H]+。
Embodiment 5:N-[3-[2-(piperidino) oxyethyl group]-the 4-aminomethyl phenyl]-3-(4-aminomethyl phenyl)-8, the preparation of 9-dihydro-7H-benzo ring heptene-6-methane amide
A. 1-[2-(2-methyl-5-nitro phenoxy group) ethyl] piperidines
Adopt the method for preparing diethyl-[2-(2-methyl-5-nitro phenoxy group) ethyl] amine in embodiment 1, by the N in embodiment 1 step j, N-diethyl ethylamine hydrochloride is replaced with 1-(2-chloroethyl) piperidine hydrochlorate, obtains yellow oil.MS[M]+＝264.3m/e。
B. 4-methyl-3-[2-(piperidino) oxyethyl group] aniline
Adopt the method for preparing 3-(2-diethylin oxyethyl group)-4-monomethylaniline in embodiment 1, by 1-[2-(the 2-methyl-5-nitro phenoxy group) ethyl that the diethyl in embodiment 1 step k-[2-(2-methyl-5-nitro phenoxy group) ethyl] amine obtains with top step a] the piperidines replacement, obtain colorless oil.MS[M]+＝234.3m/e。
C. N-[3-[2-(piperidino) oxyethyl group]-the 4-aminomethyl phenyl]-3-(4-methylbenzene Base)-8,9-dihydro-7H-benzo ring heptene-6-methane amide
Adopt the preparation method of step 1 in embodiment 1, by the 3-in step 1 (2-diethylamide base oxethyl)-4-monomethylaniline with 4-methyl-3-[2-(piperidino) oxyethyl group that obtains in the step b of top] the aniline replacement, obtain title compound.1H-NMR(400MHz，CDCl 3)δppm：1.44-1.48(m，2H)，1.59-1.64(m，4H)，2.14-2.19(m，5H)，2.40(s，3H)，2.57(m，4H)，2.69-2.73(t，2H)，2.83-2.88(m，4H)，4.15-4.18(t，2H)，6.88-7.53(m，11H)，7.63(br，1H)；FAB-MS(m/z)：495.3[M+H]+。
Embodiment 6:N-[3-[3-dimethylamino propoxy]-the 4-aminomethyl phenyl]-3-(4-aminomethyl phenyl)-8, the preparation of 9-dihydro-7H-benzo ring heptene-6-methane amide
Figure S2008100006483D00291
A. Dimethyl-[2-(2-methyl-5-nitro phenoxy group) propyl group] amine
Adopt the method for preparing diethyl-[2-(2-methyl-5-nitro phenoxy group) ethyl] amine in embodiment 1, by the N in embodiment 1 step j, N-diethyl ethylamine hydrochloride N, N-dimethyl propylene amine hydrochlorate is replaced, and obtains yellow oil.MS[M]+＝238.3m/e。
B. 3-(2-dimethylin propoxy-)-4-monomethylaniline
Adopt the method for preparing 3-(2-diethylin oxyethyl group)-4-monomethylaniline in embodiment 1, dimethyl that diethyl in embodiment 1 step k-[2-(2-methyl-5-nitro phenoxy group) ethyl] amine obtains with top step a-[2-(2-methyl-5-nitro phenoxy group) propyl group] amine is replaced, obtained colorless oil.MS[M]+＝208.3m/e。
C. N-[3-(2-dimethyl propoxy-)-4-aminomethyl phenyl]-3-(4-aminomethyl phenyl)-8,9- Dihydro-7H-benzo ring heptene-6-methane amide
Adopt the preparation method of step 1 in embodiment 1, the 3-in step 1 (2-diethylamide base oxethyl)-4-monomethylaniline is replaced with the 3-that obtains in the step b of top (2-dimethylin propoxy-)-4-monomethylaniline, obtain title compound.1H-NMR(400MHz，CDCl 3)δppm：2.13-2.17(m，5H)，2.22-2.26(m，2H)，2.39(s，3H)，2.65-2.72(m，8H)，2.85-2.88(t，2H)，3.01-3.06(t，2H)，4.05-4.09(t，2H)，6.98-7.53(m，11H)，8.00(br，1H)；FAB-MS(m/z)：469.1[M+H]+。
Embodiment 7:N-[3-[2-(1-pyrrolidyl) oxyethyl group]-the 4-aminomethyl phenyl]-3-(4-aminomethyl phenyl)-8, the preparation of 9-dihydro-7H-benzo ring heptene-6-methane amide
Figure S2008100006483D00301
A. 1-[2-(2-methyl-5-nitro phenoxy group) ethyl] tetramethyleneimine
Adopt the method for preparing diethyl-[2-(2-methyl-5-nitro phenoxy group) ethyl] amine in embodiment 1, by the N in embodiment 1 step j, N-diethyl ethylamine hydrochloride is replaced with 1-(2-chloroethyl) pyrrolidine hydrochloride, obtains yellow oil.MS[M]+＝250.3m/e。
B. 4-methyl-3-[2-(1-pyrrolidyl) oxyethyl group] aniline
Adopt the method for preparing 3-(2-diethylin oxyethyl group)-4-monomethylaniline in embodiment 1, by 1-[2-(the 2-methyl-5-nitro phenoxy group) ethyl that the diethyl in embodiment 1 step k-[2-(2-methyl-5-nitro phenoxy group) ethyl] amine obtains with top step a] the tetramethyleneimine replacement, obtain colorless oil.MS[M]+＝220.3m/e。
C. N-[3-[2-(1-pyrrolidyl) oxyethyl group]-the 4-aminomethyl phenyl]-3-(4-methylbenzene Base)-8,9-dihydro-7H-benzo ring heptene-6-methane amide
Adopt the preparation method of step 1 in embodiment 1, by the 3-in step 1 (2-diethylamide base oxethyl)-4-monomethylaniline with the 4-methyl-3-[2-that obtains in the step b of top (1-pyrrolidyl) oxyethyl group] the aniline replacement, obtain title compound.1H-NMR(400MHz，CDCl 3)δppm：1.83-1.85(m，4H)，2.12-2.20(m，5H)，2.40(s，3H)，2.69-2.73(m，6H)，2.86-2.89(t，2H)，2.97-3.01(t，2H)，4.17-4.21(t，2H)，6.92-7.52(m，11H)，7.65(br，1H)；FAB-MS(m/z)：481.3[M+H]+。
Embodiment 8:N-[3-(2-diethyl amino base oxethyl) phenyl]-3-(4-aminomethyl phenyl)-8, the preparation of 9-dihydro-7H-benzo ring heptene-6-methane amide
Figure S2008100006483D00311
A. Diethyl-[2-(5-nitro-phenoxy) ethyl] amine
Adopt the method for preparing diethyl-[2-(2-methyl-5-nitro phenoxy group) ethyl] amine in embodiment 1, the 2-methyl-5-nitro phenol in embodiment 1 step j is replaced with the 3-nitrophenols, obtain yellow oil.MS[M]+＝238.3m/e。
B. 3-(2-diethylin oxyethyl group) aniline
Adopt the method for preparing 3-(2-diethylin oxyethyl group)-4-monomethylaniline in embodiment 1, diethyl that diethyl in embodiment 1 step k-[2-(2-methyl-5-nitro phenoxy group) ethyl] amine obtains with top step a-[2-(5-nitro-phenoxy) ethyl] amine is replaced, obtained colorless oil.MS[M]+＝208.3m/e。
C. N-[3-(2-diethyl amino base oxethyl) phenyl]-3-(4-aminomethyl phenyl)-8, the 9-dihydro -7H-benzo ring heptene-6-methane amide
Adopt the preparation method of step 1 in embodiment 1, the 3-in step 1 (2-diethylamide base oxethyl)-4-monomethylaniline is replaced with the 3-that obtains in the step b of top (2-diethylin oxyethyl group) aniline, obtain title compound.1H-NMR(400MHz，CDCl 3)δppm：1.06-1.10(m，6H)，2.13-2.16(m，2H)，2.39(s，3H)，2.63-2.71(m，6H)，2.87-2.92(m，4H)，4.06-4.10(t，2H)，6.6 8-7.51(m，12H)，7.69(br，1H)；FAB-MS(m/z)：469.1[M+H]+。
Embodiment 9:N-[3-(2-diisopropylaminoethyl oxyethyl group) phenyl]-3-(4-aminomethyl phenyl)-8, the preparation of 9-dihydro-7H-benzo ring heptene-6-methane amide
A. Di-isopropyl-[2-(5-nitro-phenoxy) ethyl] amine
Adopt the method for preparing diethyl-[2-(2-methyl-5-nitro phenoxy group) ethyl] amine in embodiment 1,2-methyl-5-nitro phenol in embodiment 1 step j is replaced with the 3-nitrophenols, and by N, N-diethyl ethylamine hydrochloride N, N-diisopropylethylamine hydrochloride is replaced, and obtains yellow oil.MS[M]+＝266.3m/e。
B. 3-(2-Diisopropylamine base oxethyl) aniline
Adopt the method for preparing 3-(2-diethylin oxyethyl group)-4-monomethylaniline in embodiment 1, di-isopropyl that diethyl in embodiment 1 step k-[2-(2-methyl-5-nitro phenoxy group) ethyl] amine obtains with top step a-[2-(5-nitro-phenoxy) ethyl] amine is replaced, obtained colorless oil.MS[M]+＝236.4m/e。
C. N-[3-(2-diisopropylaminoethyl oxyethyl group) phenyl]-3-(4-aminomethyl phenyl)-8,9- Dihydro-7H-benzo ring heptene-6-methane amide
Adopt the preparation method of step 1 in embodiment 1, the 3-in step 1 (2-diethylamide base oxethyl)-4-monomethylaniline is replaced with the 3-that obtains in the step b of top (2-Diisopropylamine base oxethyl) aniline, obtain title compound.1H-NMR(400MHz，CDCl 3)δppm：1.06-1.09(d，12H)，2.15-2.17(m，2H)，2.40(s，3H)，2.71(t，2H)，2.86-2.88(m，4H)，3.09(m，2H)，3.95-3.97(t，2H)，6.67-7.52(m，12H)，7.66(br，1H)；FAB-MS(m/z)：497.0[M+H]+。
Embodiment 10:N-[3-(2-dimethylamino ethoxy) phenyl]-3-(4-aminomethyl phenyl)-8, the preparation of 9-dihydro-7H-benzo ring heptene-6-methane amide
A. Dimethyl-[2-(5-nitro-phenoxy) ethyl] amine
Adopt the method for preparing diethyl-[2-(2-methyl-5-nitro phenoxy group) ethyl] amine in embodiment 1,2-methyl-5-nitro phenol in embodiment 1 step j is replaced with the 3-nitrophenols, and by N, N-diethyl ethylamine hydrochloride N, N-dimethyl amine hydrochloride is replaced, and obtains yellow oil.MS[M]+＝210.2m/e。
B. 3-(2-dimethylamino ethoxy) aniline
Adopt the method for preparing 3-(2-diethylin oxyethyl group)-4-monomethylaniline in embodiment 1, dimethyl that diethyl in embodiment 1 step k-[2-(2-methyl-5-nitro phenoxy group) ethyl] amine obtains with top step a-[2-(5-nitro-phenoxy) ethyl] amine is replaced, obtained colorless oil.MS[M]+＝180.2m/e。
C. N-[3-(2-dimethylamino ethoxy) phenyl]-3-(4-aminomethyl phenyl)-8,9-bis- Hydrogen-7H-benzo ring heptene-6-methane amide
Adopt the preparation method of step 1 in embodiment 1, the 3-in step 1 (2-diethylamide base oxethyl)-4-monomethylaniline is replaced with the 3-that obtains in the step b of top (2-dimethylamino ethoxy) aniline, obtain title compound.1H-NMR(400MHz，CDCl 3)δppm：2.14-2.18(m，2H)，2.39(s，9H)，2.71(t，2H)，2.78-2.82(t，2H)，2.87(t，2H)，4.12-4.15(t，2H)，6.70-7.52(m，12H)，7.67(br，1H)；FAB-MS(m/z)：441.1[M+H]+。
Embodiment 11:N-[3-[2-(4-morpholinyl) oxyethyl group] phenyl]-3-(4-aminomethyl phenyl)-8, the preparation of 9-dihydro-7H-benzo ring heptene-6-methane amide
A. 4-[2-(3-nitro-phenoxy) ethyl] morpholine
Adopt the method for preparing diethyl-[2-(2-methyl-5-nitro phenoxy group) ethyl] amine in embodiment 1,2-methyl-5-nitro phenol in embodiment 1 step j is replaced with the 3-nitrophenols, and by N, N-diethyl ethylamine hydrochloride is replaced with 4-(2-chloroethyl) morpholine hydrochloride, obtains yellow solid.MS[M]+＝252.3m/e。
B. 3-[2-(4-morpholinyl) oxyethyl group] aniline
Adopt the method for preparing 3-(2-diethylin oxyethyl group)-4-monomethylaniline in embodiment 1, by 4-[2-(3-nitro-phenoxy) ethyl that the diethyl in embodiment 1 step k-[2-(2-methyl-5-nitro phenoxy group) ethyl] amine obtains with top step a] the morpholine replacement, obtain colorless oil.MS[M]+＝222.3m/e。
C. N-[3-[2-(4-morpholinyl) oxyethyl group] phenyl]-3-(4-aminomethyl phenyl)-8,9-bis- Hydrogen-7H-benzo ring heptene-6-methane amide
Adopt the preparation method of step 1 in embodiment 1, by the 3-in step 1 (2-diethylamide base oxethyl)-4-monomethylaniline with the 3-[2-that obtains in the step b of top (4-morpholinyl) oxyethyl group] the aniline replacement, obtain title compound.1H-NMR(400MHz，CDCl 3)δppm：2.13-2.19(m，2H)，2.40(s，3H)，2.61(m，4H)，2.69-2.73(t，2H)，2.81-2.89(m，4H)，3.73-3.77(t，4H)，4.14-4.18(t，2H)，6.68-7.51(m，12H)，7.67(br，1H)；FAB-MS(m/z)：483.0[M+H]+。
Embodiment 12:N-[3-[2-(piperidino) oxyethyl group] phenyl]-3-(4-aminomethyl phenyl)-8, the preparation of 9-dihydro-7H-benzo ring heptene-6-methane amide
Figure S2008100006483D00341
A. 1-[2-(3-nitro-phenoxy) ethyl] piperidines
Adopt the method for preparing diethyl-[2-(2-methyl-5-nitro phenoxy group) ethyl] amine in embodiment 1,2-methyl-5-nitro phenol in embodiment 1 step j is replaced with the 3-nitrophenols, and by N, N-diethyl ethylamine hydrochloride is replaced with 1-(2-chloroethyl) piperidine hydrochlorate, obtains yellow oil.MS[M]+＝250.3m/e。
B. 3-[2-(piperidino) oxyethyl group] aniline
Adopt the method for preparing 3-(2-diethylin oxyethyl group)-4-monomethylaniline in embodiment 1, by 1-[2-(3-nitro-phenoxy) ethyl that the diethyl in embodiment 1 step k-[2-(2-methyl-5-nitro phenoxy group) ethyl] amine obtains with top step a] the piperidines replacement, obtain colorless oil.MS[M]+＝220.3m/e。
C. N-[3-[2-(piperidino) oxyethyl group] phenyl]-3-(4-aminomethyl phenyl)-8,9-bis- Hydrogen-7H-benzo ring heptene-6-methane amide
Adopt the preparation method of step 1 in embodiment 1, by the 3-in step 1 (2-diethylamide base oxethyl)-4-monomethylaniline with 3-[2-(piperidino) oxyethyl group that obtains in the step b of top] the aniline replacement, obtain title compound.1H-NMR(400MHz，CDCl 3)δppm：1.44-1.48(m，2H)，1.59-1.66(m，4H)，2.13-2.15(m，2H)，2.39(s，3H)，2.56(m，4H)，2.67-2.72(t，2H)，2.81-2.88(m，4H)，4.13-4.16(t，2H)，6.67-7.51(m，12H)，7.75(br，1H)；FAB-MS(m/z)：481.0[M+H]+。
Embodiment 13:N-[3-[3-dimethylamino propoxy] phenyl]-3-(4-aminomethyl phenyl)-8, the preparation of 9-dihydro-7H-benzo ring heptene-6-methane amide
Figure S2008100006483D00351
A. Dimethyl-[2-(5-nitro-phenoxy) propyl group] amine
Adopt the method for preparing diethyl-[2-(2-methyl-5-nitro phenoxy group) ethyl] amine in embodiment 1,2-methyl-5-nitro phenol in embodiment 1 step j is replaced with the 3-nitrophenols, and by N, N-diethyl ethylamine hydrochloride N, N-dimethyl propylene amine hydrochlorate is replaced, and obtains yellow oil.MS[M]+＝224.3 m/e。
B. 3-(2-dimethylin propoxy-) aniline
Adopt the method for preparing 3-(2-diethylin oxyethyl group)-4-monomethylaniline in embodiment 1, dimethyl that diethyl in embodiment 1 step k-[2-(2-methyl-5-nitro phenoxy group) ethyl] amine obtains with top step a-[2-(5-nitro-phenoxy) propyl group] amine is replaced, obtained colorless oil.MS[M]+＝194.3m/e。
C. N-[3-(2-dimethylamino propoxy) phenyl]-3-(4-aminomethyl phenyl)-8,9-bis- Hydrogen-7H-benzo ring heptene-6-methane amide
Adopt the preparation method of step 1 in embodiment 1, the 3-in step 1 (2-diethylamide base oxethyl)-4-monomethylaniline is replaced with the 3-that obtains in the step b of top (2-dimethylin propoxy-) aniline, obtain title compound.1H-NMR(400MHz，CDCl 3)δppm：2.03-2.17(m，4H)，2.40(s，3H)，2.42(s，6H)，2.66-2.73(m，4H)，2.86-2.89(t，2H)，4.02-4.06(t，2H)，6.65-7.53(m，12H)，7.76(br，1H)；FAB-MS(m/z)：455.1[M+H]+。
Embodiment 14:N-[3-[2-(1-pyrrolidyl) oxyethyl group] phenyl]-3-(4-aminomethyl phenyl)-8, the preparation of 9-dihydro-7H-benzo ring heptene-6-methane amide
Figure S2008100006483D00361
A. 1-[2-(3-nitro-phenoxy) ethyl] tetramethyleneimine
Adopt the method for preparing diethyl-[2-(2-methyl-5-nitro phenoxy group) ethyl] amine in embodiment 1,2-methyl-5-nitro phenol in embodiment 1 step j is replaced with the 3-nitrophenols, and by N, N-diethyl ethylamine hydrochloride is replaced with 1-(2-chloroethyl) pyrrolidine hydrochloride, obtains yellow oil.MS[M]+＝236.3m/e。
B. 3-[2-(1-pyrrolidyl) oxyethyl group] aniline
Adopt the method for preparing 3-(2-diethylin oxyethyl group)-4-monomethylaniline in embodiment 1, by 1-[2-(3-nitro-phenoxy) ethyl that the diethyl in embodiment 1 step k-[2-(2-methyl-5-nitro phenoxy group) ethyl] amine obtains with top step a] the tetramethyleneimine replacement, obtain colorless oil.MS[M]+＝206.3m/e。
C. N-[3-[2-(1-pyrrolidyl) oxyethyl group] phenyl]-3-(4-aminomethyl phenyl)-8,9- Dihydro-7 H-benzo ring heptene-6-methane amide
Adopt the preparation method of step 1 in embodiment 1, by the 3-in step 1 (2-diethylamide base oxethyl)-4-monomethylaniline with the 3-[2-that obtains in the step b of top (1-pyrrolidyl) oxyethyl group] the aniline replacement, obtain title compound.1H-NMR(400MHz，CDCl 3)δppm：1.81-1.85(m，4H)，2.14-2.18(m，4H)，2.39(s，3H)，2.68-2.72(m，6H)，2.85-2.89(t，2H)，2.94-2.97(t，2H)，4.15-4.18(t，2H)，6.69-7.52(m，12H)，7.71(br，1H)；FAB-MS(m/z)：467.0[M+H]+。
Embodiment 15:N-[3-(2-diethyl amino base oxethyl)-4-p-methoxy-phenyl]-3-(4-aminomethyl phenyl)-8, the preparation of 9-dihydro-7H-benzo ring heptene-6-methane amide
Figure S2008100006483D00371
A. Diethyl-[2-(2-methoxyl group-5-nitro-phenoxy) ethyl] amine
Adopt the method for preparing diethyl-[2-(2-methyl-5-nitro phenoxy group) ethyl] amine in embodiment 1, the 2-methyl-5-nitro phenol in embodiment 1 step j is replaced with 2-methoxyl group-5-nitrophenols, obtain yellow oil.MS[M]+＝268.3m/e。
B. 3-(2-diethylin oxyethyl group)-4-anisidine
Adopt the method for preparing 3-(2-diethylin oxyethyl group)-4-monomethylaniline in embodiment 1, diethyl that diethyl in embodiment 1 step k-[2-(2-methyl-5-nitro phenoxy group) ethyl] amine obtains with top step a-[2-(2-methoxyl group-5-nitro-phenoxy) ethyl] amine is replaced, obtained colorless oil.MS[M]+238.3m/e。
C. N-[3-(2-diethyl amino base oxethyl)-4-p-methoxy-phenyl]-3-(4-methylbenzene Base)-8,9-dihydro-7H-benzo ring heptene-6-methane amide
Adopt the preparation method of step 1 in embodiment 1, the 3-in step 1 (2-diethylamide base oxethyl)-4-monomethylaniline is replaced with the 3-that obtains in the step b of top (2-diethylin oxyethyl group)-4-anisidine, obtain title compound.1H-NMR(400MHz，DMSO-d 6)δppm：0.92-0.97(t，6H)，1.95-2.00(m，2H)，2.30(s，3H)，2.51-2.58(m，6H)，2.75-2.81(m，4H)，3.69(s，3H)，3.90-3.94(t，2H)，6.86-7.63(m，11H)，9.77(s，1H)；FAB-MS(m/z)：499.3[M+H]+。
Embodiment 16:N-[3-(2-diisopropylaminoethyl oxyethyl group)-4-p-methoxy-phenyl]-3-(4-aminomethyl phenyl)-8, the preparation of 9-dihydro-7H-benzo ring heptene-6-methane amide
Figure S2008100006483D00372
A. Di-isopropyl-[2-(2-methoxyl group-5-nitro-phenoxy) ethyl] amine
Adopt the method for preparing diethyl-[2-(2-methyl-5-nitro phenoxy group) ethyl] amine in embodiment 1,2-methyl-5-nitro phenol in embodiment 1 step j is replaced with 2-methoxyl group-5-nitrophenols, and by N, N-diethyl ethylamine hydrochloride N, N-diisopropylethylamine hydrochloride is replaced, and obtains yellow oil.MS[M]+＝296.4m/e。
B. 3-(2-Diisopropylamine base oxethyl)-4-anisidine
Adopt the method for preparing 3-(2-diethylin oxyethyl group)-4-monomethylaniline in embodiment 1, di-isopropyl that diethyl in embodiment 1 step k-[2-(2-methyl-5-nitro phenoxy group) ethyl] amine obtains with top step a-[2-(2-methoxyl group-5-nitro-phenoxy) ethyl] amine is replaced, obtained colorless oil.MS[M]+＝266.4m/e。
C. N-[3-(2-diisopropylaminoethyl oxyethyl group)-4-p-methoxy-phenyl]-3-(4-methylbenzene Base)-8,9-dihydro-7H-benzo ring heptene-6-methane amide
Adopt the preparation method of step 1 in embodiment 1, the 3-in step 1 (2-diethylamide base oxethyl)-4-monomethylaniline is replaced with the 3-that obtains in the step b of top (2-Diisopropylamine base oxethyl)-4-anisidine, obtain title compound.1H-NMR(400MHz，DMSO-d 6)δppm：0.98-1.01(d，12H)，2.01-2.04(m，2H)，2.34(s，3H)，2.59-2.63(t，2H)，2.79-2.85(m，4H)，3.00-3.04(m，2H)，3.73(s，3H)，3.79-3.83(t，2H)，6.89-7.66(m，11H)，9.78(s，1H)；FAB-MS(m/z)：527.4[M+H]+。
Embodiment 17:N-[3-(2-dimethylamino ethoxy)-4-p-methoxy-phenyl]-3-(4-aminomethyl phenyl)-8, the preparation of 9-dihydro-7H-benzo ring heptene-6-methane amide
Figure S2008100006483D00381
A. Dimethyl-[2-(2-methoxyl group-5-nitro-phenoxy) ethyl] amine
Adopt the method for preparing diethyl-[2-(2-methyl-5-nitro phenoxy group) ethyl] amine in embodiment 1,2-methyl-5-nitro phenol in embodiment 1 step j is replaced with 2-methoxyl group-5-nitrophenols, and by N, N-diethyl ethylamine hydrochloride N, N-dimethyl amine hydrochloride is replaced, and obtains yellow oil.MS[M]+＝240.3m/e。
B. 3-(2-dimethylamino ethoxy)-4-anisidine
Adopt the method for preparing 3-(2-diethylin oxyethyl group)-4-monomethylaniline in embodiment 1, dimethyl that diethyl in embodiment 1 step k-[2-(2-methyl-5-nitro phenoxy group) ethyl] amine obtains with top step a-[2-(2-methoxyl group-5-nitro-phenoxy) ethyl] amine is replaced, obtained colorless oil.MS[M]+＝210.3m/e。
C. N-[3-(2-dimethylamino ethoxy)-4-p-methoxy-phenyl]-3-(4-methylbenzene Base)-8,9-dihydro-7H-benzo ring heptene-6-methane amide
Adopt the preparation method of step 1 in embodiment 1, the 3-in step 1 (2-diethylamide base oxethyl)-4-monomethylaniline is replaced with the 3-that obtains in the step b of top (2-dimethylamino ethoxy)-4-anisidine, obtain title compound.1H-NMR(400MHz，DMSO-d 6)δppm：1.95-2.00(m，2H)，2.20(s，6H)，2.30(s，3H)，2.55-2.65(m，4H)，2.77-2.81(t，2H)，3.70(s，3H)，3.95-3.99(t，2H)，6.86-7.63(m，11H)，9.78(s，1H)；FAB-MS(m/z)：471.3[M+H]+。
Embodiment 18:N-[3-[2-(4-morpholinyl) oxyethyl group]-the 4-p-methoxy-phenyl]-3-(4-aminomethyl phenyl)-8, the preparation of 9-dihydro-7H-benzo ring heptene-6-methane amide
Figure S2008100006483D00391
A. 4-[2-(2-methoxyl group-5-nitro-phenoxy) ethyl] morpholine
Adopt the method for preparing diethyl-[2-(2-methyl-5-nitro phenoxy group) ethyl] amine in embodiment 1,2-methyl-5-nitro phenol in embodiment 1 step j is replaced with 2-methoxyl group-5-nitrophenols, and by N, N-diethyl ethylamine hydrochloride is replaced with 4-(2-chloroethyl) morpholine hydrochloride, obtains yellow solid.MS[M]+＝282.3m/e。
B. 3-[2-(4-morpholinyl) oxyethyl group]-the 4-anisidine
Adopt the method for preparing 3-(2-diethylin oxyethyl group)-4-monomethylaniline in embodiment 1, by 4-[2-(2-methoxyl group-5-nitro-phenoxy) ethyl that the diethyl in embodiment 1 step k-[2-(2-methyl-5-nitro phenoxy group) ethyl] amine obtains with top step a] the morpholine replacement, obtain colorless oil.MS[M]+＝252.3m/e。
C. N-[3-[2-(4-morpholinyl) oxyethyl group]-the 4-p-methoxy-phenyl]-3-(4-methylbenzene Base)-8,9-dihydro-7H-benzo ring heptene-6-methane amide
Adopt the preparation method of step 1 in embodiment 1, by the 3-in step 1 (2-diethylamide base oxethyl)-4-monomethylaniline with the 3-[2-that obtains in the step b of top (4-morpholinyl) oxyethyl group]-replacement of 4-anisidine, obtain title compound.1H-NMR(400MHz，CDCl 3)δppm：2.15-2.17(m，2H)，2.40(s，3H)，2.64-2.73(m，6H)，2.88-2.91(m，4H)，3.74-3.77(m，4H)，3.85(s，3H)，4.20-4.23(t，2H)，6.83-7.52(m，11H)，7.62(br，1H)；FAB-MS(m/z)：513.3[M+H]+。
Embodiment 19:N-[3-[2-(piperidino) oxyethyl group]-the 4-p-methoxy-phenyl]-3-(4-aminomethyl phenyl)-8, the preparation of 9-dihydro-7H-benzo ring heptene-6-methane amide
Figure S2008100006483D00401
A. 1-[2-(2-methoxyl group-5-nitro-phenoxy) ethyl] piperidines
Adopt the method for preparing diethyl-[2-(2-methyl-5-nitro phenoxy group) ethyl] amine in embodiment 1,2-methyl-5-nitro phenol in embodiment 1 step j is replaced with 2-methoxyl group-5-nitrophenols, and by N, N-diethyl ethylamine hydrochloride is replaced with 1-(2-chloroethyl) piperidine hydrochlorate, obtains yellow oil.MS[M]+＝280.3m/e。
B. 3-[2-(piperidino) oxyethyl group]-the 4-anisidine
Adopt the method for preparing 3-(2-diethylin oxyethyl group)-4-monomethylaniline in embodiment 1, by 1-[2-(2-methoxyl group-5-nitro-phenoxy) ethyl that the diethyl in embodiment 1 step k-[2-(2-methyl-5-nitro phenoxy group) ethyl] amine obtains with top step a] the piperidines replacement, obtain colorless oil.MS[M]+＝250.3m/e。
C. N-[3-[2-(piperidino) oxyethyl group]-the 4-p-methoxy-phenyl]-3-(4-methylbenzene Base)-8,9-dihydro-7H-benzo ring heptene-6-methane amide
Adopt the preparation method of step 1 in embodiment 1, by the 3-in step 1 (2-diethylamide base oxethyl)-4-monomethylaniline with 3-[2-(piperidino) oxyethyl group that obtains in the step b of top]-replacement of 4-anisidine, obtain title compound.1H-NMR(400MHz，DMSO-d 6)δppm：1.33-1.48(m，6H)，1.95-2.00(m，2H)，2.30(s，3H)，2.41-2.47(m，4H)，2.55-2.65(m，4H)，2.77-2.81(t，2H)，3.70(s，3H)，3.96-4.00(t，2H)，6.86-7.63(m，11H)，9.78(s，1H)；FAB-MS(m/z)：511.3[M+H]+。
Embodiment 20:N-[3-[3-dimethylamino propoxy]-the 4-p-methoxy-phenyl]-3-(4-aminomethyl phenyl)-8, the preparation of 9-dihydro-7H-benzo ring heptene-6-methane amide
Figure S2008100006483D00411
A. Dimethyl-[2-(2-methoxyl group-5-nitro-phenoxy) propyl group] amine
Adopt the method for preparing diethyl-[2-(2-methyl-5-nitro phenoxy group) ethyl] amine in embodiment 1,2-methyl-5-nitro phenol in embodiment 1 step j is replaced with 2-methoxyl group-5-nitrophenols, and by N, N-diethyl ethylamine hydrochloride N, N-dimethyl propylene amine hydrochlorate is replaced, and obtains yellow oil.MS[M]+＝254.3m/e。
B. 3-(2-dimethylin propoxy-)-4-anisidine
Adopt the method for preparing 3-(2-diethylin oxyethyl group)-4-monomethylaniline in embodiment 1, dimethyl that diethyl in embodiment 1 step k-[2-(2-methyl-5-nitro phenoxy group) ethyl] amine obtains with top step a-[2-(2-methoxyl group-5-nitro-phenoxy) propyl group] amine is replaced, obtained colorless oil.MS[M]+＝224.3m/e。
C. N-[3-(2-dimethylamino propoxy)-4-p-methoxy-phenyl]-3-(4-methylbenzene Base)-8,9-dihydro-7H-benzo ring heptene-6-methane amide
Adopt the preparation method of step 1 in embodiment 1, the 3-in step 1 (2-diethylamide base oxethyl)-4-monomethylaniline is replaced with the 3-that obtains in the step b of top (2-dimethylin propoxy-)-4-anisidine, obtain title compound.1H-NMR(400MHz，CDCl 3)δppm：2.13-2.19(m，2H)，2.32-2.39(m，5H)，2.70-2.88(m，10H)，3.21-3.25(t，2H)，3.84(s，3H)，4.12-4.16(t，2H)，6.83-7.56(m，11H)，8.12(s，1H)；FAB-MS(m/z)：485.0[M+H]+。
Embodiment 21:N-[3-[2-(1-pyrrolidyl) oxyethyl group]-the 4-p-methoxy-phenyl]-3-(4-aminomethyl phenyl)-8, the preparation of 9-dihydro-7H-benzo ring heptene-6-methane amide
Figure S2008100006483D00421
A. 1-[2-(2-methoxyl group-5-nitro-phenoxy) ethyl] tetramethyleneimine
Adopt the method for preparing diethyl-[2-(2-methyl-5-nitro phenoxy group) ethyl] amine in embodiment 1,2-methyl-5-nitro phenol in embodiment 1 step j is replaced with 2-methoxyl group-5-nitrophenols, and by N, N-diethyl ethylamine hydrochloride is replaced with 1-(2-chloroethyl) pyrrolidine hydrochloride, obtains yellow oil.MS[M]+＝266.3m/e。
B. 3-[2-(1-pyrrolidyl) oxyethyl group]-the 4-anisidine
Adopt the method for preparing 3-(2-diethylin oxyethyl group)-4-monomethylaniline in embodiment 1, by 1-[2-(2-methoxyl group-5-nitro-phenoxy) ethyl that the diethyl in embodiment 1 step k-[2-(2-methyl-5-nitro phenoxy group) ethyl] amine obtains with top step a] the tetramethyleneimine replacement, obtain colorless oil.MS[M]+＝236.3m/e。
C. N-[3-[2-(1-pyrrolidyl) oxyethyl group]-the 4-p-methoxy-phenyl]-3-(4-methylbenzene Base)-8,9-dihydro-7H-benzo ring heptene-6-methane amide
Adopt the preparation method of step 1 in embodiment 1, by the 3-in step 1 (2-diethylamide base oxethyl)-4-monomethylaniline with the 3-[2-that obtains in the step b of top (1-pyrrolidyl) oxyethyl group]-the 4-anisidine replaces, and obtains title compound.1H-NMR(400MHz，CDCl 3)δppm：1.79-1.83(m，4H)，2.13-2.17(m，2H)，2.40(s，3H)，2.65-2.73(m，6H)，2.86-3.00(m，4H)，3.85(s，3H)，4.17-4.22(t，2H)，6.82-7.52(m，11H)，7.61(br，1H)；FAB-MS(m/z)：497.4[M+H]+。
Embodiment 22:N-[3-(2-diethyl amino base oxethyl)-4-aminomethyl phenyl]-the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide;
Figure S2008100006483D00431
A. 4-(4-bromine phenoxy group) ethyl butyrate
P bromophenol (0.032mmol) and 4-bromo-butyric acid ethyl ester (0.035mol) are dissolved in DMF (20ml), add salt of wormwood (0.064mol), stirred overnight at room temperature.Reaction mixture is poured in mixture of ice and water, add ethyl acetate, separate organic phase.The water ethyl acetate extraction, merge organic phase, water and saturated common salt washing.Anhydrous magnesium sulfate drying, filter, and is spin-dried for and obtains colorless oil.MS[M]3＝257.1m/e。
B. 4-(4-bromine phenoxy group) butyric acid
The colorless oil (0.03mol) that top step a is obtained is dissolved in methyl alcohol (18ml), adds 3N sodium hydroxide solution (32ml), reflux half an hour.Be spin-dried for methyl alcohol, add the water dilution, use the ether extraction water, organic phase discards.The water hcl acidifying, use ethyl acetate extraction, combining extraction liquid, water and saturated common salt washing.Anhydrous magnesium sulfate drying, filter, and is spin-dried for, and obtains white solid.MS[M]+＝259.1m/e。
C. 3-is bromo-6,7-dihydro-8H-9-oxa-benzo ring heptene-5-ketone
Adopt the preparation method of steps d in embodiment 1, the 4-bromobenzene valeric acid in steps d is replaced with the 4-that obtains in the step b of top (4-bromine phenoxy group) butyric acid, obtain yellow oil.1H-NMR(400MHz，CDCl 3)δppm：2.20-2.24(m，2H)，2.87-2.91(t，2H)，4.21-4.26(t，2H)，6.95-7.87(m，3H)。
D. 3-(4-aminomethyl phenyl)-6,7-dihydro-8H-9-oxa-benzo ring heptene-5-ketone
Adopt the preparation method of step e in embodiment 1, the 3-in step e is bromo-6,7,8, and 9-tetrahydrochysene-5H-benzo ring heptene-5-ketone is bromo-6 with the 3-that obtains in the step c of top, and 7-dihydro-8H-9-oxa-benzo ring heptene-5-ketone replacement, obtain white solid.1H-NMR(400MHz，CDCl 3)δppm：2.23-2.27(m，2H)，2.39(s，3H)，2.92-2.96(t，2H)，4.6-4.30(t，2H)，7.12-8.00(m，7H)。
E. 3-(4-aminomethyl phenyl)-5,6,7,8-tetrahydrochysene-9-oxa-benzo ring heptene-5-ketone-6-first The acid methyl esters
Adopt the preparation method of step f in embodiment 1, by the 3-in step f (4-aminomethyl phenyl)-6,7,8,9-tetrahydrochysene-5H-benzo ring heptene-5-ketone is with the 3-that obtains in the steps d of top (4-aminomethyl phenyl)-6,7-dihydro-8H-9-oxa-benzo ring heptene-5-ketone is replaced, and obtains white solid.MS[M]+＝310.4m/e。
F. 3-(4-aminomethyl phenyl)-5-hydroxyl-5,6,7,8-tetrahydrochysene-9-oxa-benzo ring heptene -6-methyl-formiate
Adopt the preparation method of step g in embodiment 1, by the 3-in step g (4-aminomethyl phenyl)-6,7,8,9-tetrahydrochysene-5H-benzo ring heptene-5-ketone-6-methyl-formiate is with the 3-that obtains in the step e of top (4-aminomethyl phenyl)-5,6,7,8-tetrahydrochysene-9-oxa-benzo ring heptene-5-ketone-6-methyl-formiate is replaced, and obtains white solid.MS[M]+＝312.4m/e。
G. 3-(4-aminomethyl phenyl)-5-hydroxyl-5,6,7,8-tetrahydrochysene-9-oxa-benzo ring heptene -6-formic acid
The white solid (1.1mmol) that top step f is obtained is placed in the 50ml round-bottomed flask, adds 1mol/L sodium hydroxide solution (10ml), methyl alcohol (5ml), ether (4ml), stirring at room 30 minutes.Reaction mixture is spin-dried for, and adds the water dilution, uses the ether extraction water, and organic phase discards.With 1mol/L hydrochloric acid, regulate below pH value to 5, use ethyl acetate extraction, combining extraction liquid, water and saturated common salt washing.Anhydrous magnesium sulfate drying, filter, and is spin-dried for, and obtains white solid.MS[M]+＝298.3m/e。
H. 3-(4-aminomethyl phenyl)-7, the 8-dihydro-9-oxy benzo ring heptene-6-formic acid of mixing
The white solid (1.2mmol) that the top step g is obtained is placed in the 10ml round-bottomed flask, adds hydrochloric acid (1ml), diglyme (5ml), and 100 ℃ were heated 40 minutes.Reaction solution is poured into water, and uses ethyl acetate extraction, merges organic phase, water and saturated common salt washing, and anhydrous magnesium sulfate drying, filter, and is spin-dried for, and resulting product, with ethyl acetate and sherwood oil recrystallization, obtains white solid.1H-NMR(400MHz，DMSO-d 6)δppm：2.33(s，3H)，2.86-2.89(t，2H)，4.23-4.29(t，2H)，7.01-7.81(m，8H)，12.55(s，1H)。
I. N-[3-(2-diisopropyl ammonia base oxethyl)-4-aminomethyl phenyl]-3-(4-methylbenzene Base)-8,9-dihydro-7H-benzo ring heptene-6-methane amide
Adopt the preparation method of step 1 in embodiment 1, by the 3-in step 1 (4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-formic acid is with the 3-that obtains in the step h of top (4-aminomethyl phenyl)-7, mix benzo ring heptene-6-formic acid of 8-dihydro-9-oxy is replaced, and obtains title compound.1H-NMR(400MHz，CDCl 3)δppm：1.25-1.30(t，6H)，2.11(s，3H)，2.37(s，3H)，3.06-3.08(m，6H)，3.33(t，2H)，4.31-4.39(m，4H)，7.01-7.60(m，11H)，8.28(br，1H)；FAB-MS(m/z)：485.2[M+H]+。
Embodiment 23:N-[3-(2-diisopropylaminoethyl oxyethyl group)-4-aminomethyl phenyl]-preparation of the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide
Figure S2008100006483D00451
Adopt the preparation method of step 1 in embodiment 1, by the 3-in step 1 (4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-formic acid is with the 3-(4-aminomethyl phenyl)-7 that obtains in embodiment 22 step h, mix benzo ring heptene-6-formic acid of 8-dihydro-9-oxy is replaced, and the 3-that (2-diethylin oxyethyl group)-the 4-monomethylaniline obtains with b step in embodiment 2 of the 3-in step 1 (2-Diisopropylamine base oxethyl)-4-monomethylaniline is replaced, obtain title compound.1H-NMR(400MHz，CDCl 3)δppm：1.34-1.36(d，12H)，2.14(s，3H)，2.38(s，3H)，3.07-3.24(m，4H)，3.54(t，2H)，4.31-4.39(m，4H)，7.02-7.59(m，11H)，8.25(br，1H)；FAB-MS(m/z)：513.2[M+H]+。
Embodiment 24:N-[3-(2-dimethylamino ethoxy)-4-aminomethyl phenyl]-preparation of the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide
Figure S2008100006483D00452
Adopt the preparation method of step 1 in embodiment 1, by the 3-in step 1 (4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-formic acid is with the 3-(4-aminomethyl phenyl)-7 that obtains in embodiment 22 step h, mix benzo ring heptene-6-formic acid of 8-dihydro-9-oxy is replaced, and the 3-(2-dimethylamino ethoxy) that (2-diethylin oxyethyl group)-the 4-monomethylaniline obtains with b step in embodiment 3 of the 3-in step 1-4-monomethylaniline is replaced, obtain title compound.1H-NMR(400MHz，CDCl 3)δppm：2.20(s，3H)，2.38-2.40(m，9H)，2.80-2.83(t，2H)，3.06-3.08(t，2H)，4.11-4.14(t，2H)，4.33-4.35(t，2H)，6.87-7.52(m，11H)，7.62(br，1H)；FAB-MS(m/z)：457.1[M+H]+。
Embodiment 25:N-[3-[2-(4-morpholinyl) oxyethyl group]-the 4-aminomethyl phenyl]-preparation of the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide
Figure S2008100006483D00461
Adopt the preparation method of step 1 in embodiment 1, by the 3-in step 1 (4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-formic acid is with the 3-(4-aminomethyl phenyl)-7 that obtains in embodiment 22 step h, mix benzo ring heptene-6-formic acid of 8-dihydro-9-oxy is replaced, and by 4-methyl-3-[2-(4-morpholinyl) oxyethyl group that (2-diethylin oxyethyl group)-the 4-monomethylaniline obtains with b step in embodiment 4 of the 3-in step 1] the aniline replacement, obtain title compound.1H-NMR(400MHz，CDCl 3)δppm：2.19(s，3H)，2.39(s，3H)，2.63(m，4H)，2.88-2.87(t，2H)，3.05-3.07(t，2H)，3.73-3.75(t，4H)，4.15-4.18(t，2H)，4.34-4.37(t，2H)，6.83-7.58(m，11H)，7.66(br，1H)；FAB-MS(m/z)：499.1[M+H]+。
Embodiment 26:N-[3-[2-(piperidino) oxyethyl group]-the 4-aminomethyl phenyl]-preparation of the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide
Figure S2008100006483D00462
Adopt the preparation method of step 1 in embodiment 1, by the 3-in step 1 (4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-formic acid is with the 3-(4-aminomethyl phenyl)-7 that obtains in embodiment 22 step h, mix benzo ring heptene-6-formic acid of 8-dihydro-9-oxy is replaced, and 4-methyl-3-[2-(piperidino) oxyethyl group that the 3-in step 1 (2-diethylin oxyethyl group)-4-monomethylaniline is obtained with b step in embodiment 5] aniline replaces, and obtains title compound.1H-NMR(400MHz，CDCl 3)δppm：1.53(m，2H)，1.76-1.81(m，4H)，2.16(s，3H)，2.39(s，3H)，2.86(m，4H)，3.08-3.12(m，4H)，4.30-4.36(m，4H)，7.03-7.56(m，11H)，7.88(br，1H)；FAB-MS(m/z)：497.2[M+H]+。
Embodiment 27:N-[3-[3-dimethylamino propoxy]-the 4-aminomethyl phenyl]-preparation of the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide
Figure S2008100006483D00471
Adopt the preparation method of step 1 in embodiment 1, by the 3-in step 1 (4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-formic acid is with the 3-(4-aminomethyl phenyl)-7 that obtains in embodiment 22 step h, mix benzo ring heptene-6-formic acid of 8-dihydro-9-oxy is replaced, and the 3-that (2-diethylin oxyethyl group)-the 4-monomethylaniline obtains with b step in embodiment 6 of the 3-in step 1 (2-dimethylin propoxy-)-4-monomethylaniline is replaced, obtain title compound.1H-NMR(400MHz，CDCl 3)δppm：2.07-2.11(m，2H)，2.18(s，3H)，2.39(s，3H)，2.42(s，6H)，2.66-2.71(t，2H)，3.06-3.09(t，2H)，4.03-4.07(t，2H)，4.33-4.36(t，2H)，6.94-7.54(m，11H)，7.78(br，1H)；FAB-MS(m/z)：471.1[M+H]+。
Embodiment 28:N-[3-[2-(1-pyrrolidyl) oxyethyl group]-the 4-aminomethyl phenyl]-preparation of the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide
Figure S2008100006483D00472
Adopt the preparation method of step 1 in embodiment 1, by the 3-in step 1 (4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-formic acid is with the 3-(4-aminomethyl phenyl)-7 that obtains in embodiment 22 step h, mix benzo ring heptene-6-formic acid of 8-dihydro-9-oxy is replaced, and by 4-methyl-3-[2-(1-pyrrolidyl) oxyethyl group that (2-diethylin oxyethyl group)-the 4-monomethylaniline obtains with b step in embodiment 7 of the 3-in step 1] the aniline replacement, obtain title compound.1H-NMR(400MHz，CDCl 3)δppm：1.82-1.85(m，4H)，2.19(s，3H)，2.39(s，3H)，2.73-2.79(m，4H)，2.99-3.06(m，4H)，4.16-4.36(m，4H)，7.03-7.64(m，11H)，7.77(br，1H)；FAB-MS(m/z)：483.1[M+H]+。
Embodiment 29:N-[3-(2-diethyl amino base oxethyl) phenyl]-preparation of the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide
Figure S2008100006483D00481
Adopt the preparation method of step 1 in embodiment 1, by the 3-in step 1 (4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-formic acid is with the 3-(4-aminomethyl phenyl)-7 that obtains in embodiment 22 step h, mix benzo ring heptene-6-formic acid of 8-dihydro-9-oxy is replaced, and the 3-that (2-diethylin oxyethyl group)-the 4-monomethylaniline obtains with b step in embodiment 8 of the 3-in step 1 (2-diethylin oxyethyl group) aniline is replaced, obtain title compound.1H-NMR(400MHz，CDCl 3)δppm：1.07-1.11(t，6H)，2.39(s，3H)，2.65-2.71(m，4H)，2.90-2.94(t，2H)，3.04-3.06(t，2H)，4.07-4.11(t，2H)，4.32-4.35(t，2H)，6.67-7.51(m，12H)，7.71(br，1H)；FAB-MS(m/z)：471.1[M+H]+。
Embodiment 30:N-[3-(2-diisopropylaminoethyl oxyethyl group) phenyl]-preparation of the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide
Figure S2008100006483D00482
Adopt the preparation method of step 1 in embodiment 1, by the 3-in step 1 (4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-formic acid is with the 3-(4-aminomethyl phenyl)-7 that obtains in embodiment 22 step h, mix benzo ring heptene-6-formic acid of 8-dihydro-9-oxy is replaced, and the 3-that (2-diethylin oxyethyl group)-the 4-monomethylaniline obtains with b step in embodiment 9 of the 3-in step 1 (2-Diisopropylamine base oxethyl) aniline is replaced, obtain title compound.1H-NMR(400MHz，CDCl 3)δppm：1.24-1.26(d，12H)，2.39(s，3H)，3.07-3.38(m，6H)，4.23-4.36(m，4H)，6.67-7.55(m，12H)，7.92(br，1H)；FAB-MS(m/z)：499.1[M+H]+。
Embodiment 31:N-[3-(2-dimethylamino ethoxy) phenyl]-preparation of the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide
Figure S2008100006483D00491
Adopt the preparation method of step 1 in embodiment 1, by the 3-in step 1 (4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-formic acid is with the 3-(4-aminomethyl phenyl)-7 that obtains in embodiment 22 step h, mix benzo ring heptene-6-formic acid of 8-dihydro-9-oxy is replaced, and 3-(2-dimethylamino ethoxy) aniline that (2-diethylin oxyethyl group)-the 4-monomethylaniline obtains with b step in embodiment 10 of the 3-in step 1 is replaced, obtain title compound.1H-NMR(400MHz，CDCl 3)δppm：2.36-2.40(d，9H)，2.78-2.80(t，2H)，3.06-3.08(t，2H)，4.10-4.12(t，2H)，4.34-4.36(t，2H)，6.70-7.52(m，12H)，7.65(br，1H)；FAB-MS(m/z)：443.0[M+H]+。
Embodiment 32:N-[3-[2-(4-morpholinyl) oxyethyl group] phenyl]-preparation of the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide
Figure S2008100006483D00492
Adopt the preparation method of step 1 in embodiment 1, by the 3-in step 1 (4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-formic acid is with the 3-(4-aminomethyl phenyl)-7 that obtains in embodiment 22 step h, mix benzo ring heptene-6-formic acid of 8-dihydro-9-oxy is replaced, and by 3-[2-(4-morpholinyl) oxyethyl group that (2-diethylin oxyethyl group)-the 4-monomethylaniline obtains with b step in embodiment 11 of the 3-in step 1] the aniline replacement, obtain title compound.1H-NMR(400MHz，CDCl 3)δppm：2.39(t，3H)，2.63-3.06(m，8H)，3.76(t，4H)，4.12-4.16(t，2H)，4.34-4.36(t，2H)，6.68-7.52(m，12H)，7.63(br，1H)；FAB-MS(m/z)：485.1[M+H]+。
Embodiment 33:N-[3-[2-(piperidino) oxyethyl group] phenyl]-preparation of the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide
Figure S2008100006483D00501
Adopt the preparation method of step 1 in embodiment 1, by the 3-in step 1 (4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-formic acid is with the 3-(4-aminomethyl phenyl)-7 that obtains in embodiment 22 step h, mix benzo ring heptene-6-formic acid of 8-dihydro-9-oxy is replaced, and by 3-[2-(piperidino) oxyethyl group that (2-diethylin oxyethyl group)-the 4-monomethylaniline obtains with b step in embodiment 12 of the 3-in step 1] the aniline replacement, obtain title compound.1H-NMR(400MHz，CDCl 3)δppm：1.78-2.20(m，6H)，2.38(s，3H)，2.75(t，2H)，3.06-3.09(t，2H)，3.30-3.32(t，2H)，3.54-3.57(t，2H)，4.31-4.34(t，2H)，4.46-4.49(t，2H)，6.59-7.61(m，12H)，8.36(br，1H)；FAB-MS(m/z)：483.1[M+H]+。
Embodiment 34:N-[3-[3-dimethylamino propoxy] phenyl]-preparation of the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide
Figure S2008100006483D00502
Adopt the preparation method of step 1 in embodiment 1, by the 3-in step 1 (4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-formic acid is with the 3-(4-aminomethyl phenyl)-7 that obtains in embodiment 22 step h, mix benzo ring heptene-6-formic acid of 8-dihydro-9-oxy is replaced, and the 3-that (2-diethylin oxyethyl group)-the 4-monomethylaniline obtains with b step in embodiment 13 of the 3-in step 1 (2-dimethylin propoxy-) aniline is replaced, obtain title compound.1H-NMR(400MHz，CDCl 3)δppm：2.16-2.21(m，2H)，2.38(s，3H)，2.61(s，6H)，2.92-3.00(t，2H)，3.05-3.08(t，2H)，4.01-4.05(t，2H)，4.31-4.34(t，2H)，6.62-7.55(m，12H)，8.07(br，1H)；FAB-MS(m/z)：457.1[M+H]+。
Embodiment 35:N-[3-[2-(1-pyrrolidyl) oxyethyl group] phenyl]-preparation of the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide
Figure S2008100006483D00511
Adopt the preparation method of step 1 in embodiment 1, by the 3-in step 1 (4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-formic acid is with the 3-(4-aminomethyl phenyl)-7 that obtains in embodiment 22 step h, mix benzo ring heptene-6-formic acid of 8-dihydro-9-oxy is replaced, and by 3-[2-(1-pyrrolidyl) oxyethyl group that (2-diethylin oxyethyl group)-the 4-monomethylaniline obtains with b step in embodiment 14 of the 3-in step 1] the aniline replacement, obtain title compound.1H-NMR(400MHz，CDCl 3)δppm：1.83(m，4H)，2.39(s，3H)，2.68(m，4H)，2.92-2.96(t，2H)，3.06-3.08(t，2H)，4.14-4.17(t，2H)，4.33-4.36(t，2H)，6.70-7.52(m，12H)，7.65(br，1H)；FAB-MS(m/z)：469.0[M+H]+。
Embodiment 36:N-[3-(2-diethyl amino base oxethyl)-4-p-methoxy-phenyl]-preparation of the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide
Figure S2008100006483D00521
Adopt the preparation method of step 1 in embodiment 1, by the 3-in step 1 (4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-formic acid is with the 3-(4-aminomethyl phenyl)-7 that obtains in embodiment 22 step h, mix benzo ring heptene-6-formic acid of 8-dihydro-9-oxy is replaced, and the 3-that (2-diethylin oxyethyl group)-the 4-monomethylaniline obtains with b step in embodiment 15 of the 3-in step 1 (2-diethylin oxyethyl group)-4-anisidine is replaced, obtain title compound.1H-NMR(400MHz，CDCl 3)δppm：1.29-1.34(t，6H)，2.38(s，3H)，3.08-3.15(m，6H)，3.33-3.37(t，2H)，3.79(s，3H)，4.31-4.34(t，2H)，4.40-4.43(t，2H)，6.79-7.62(m，11H)，8.32(br，1H)；FAB-MS(m/z)：501.0[M+H]+。
Embodiment 37:N-[3-(2-diisopropylaminoethyl oxyethyl group)-4-p-methoxy-phenyl]-preparation of the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide
Figure S2008100006483D00522
Adopt the preparation method of step 1 in embodiment 1, by the 3-in step 1 (4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-formic acid is with the 3-(4-aminomethyl phenyl)-7 that obtains in embodiment 22 step h, mix benzo ring heptene-6-formic acid of 8-dihydro-9-oxy is replaced, and the 3-that (2-diethylin oxyethyl group)-the 4-monomethylaniline obtains with b step in embodiment 16 of the 3-in step 1 (2-Diisopropylamine base oxethyl)-4-anisidine is replaced, obtain title compound.1H-NMR(400MHz，CDCl 3)δppm：1.43-1.52(m，12H)，2.38(s，3H)，3.09-3.12(t，2H)，3.38-3.40(m，2H)，3.71-3.74(m，2H)，3.82(s，3H)，4.32-4.36(t，2H)，4.60-4.64(t，2H)，6.81-7.63(m，11H)，8.34(br，1H)；FAB-MS(m/z)：529.1[M+H]+。
Embodiment 38:N-[3-(2-dimethylamino ethoxy)-4-p-methoxy-phenyl]-preparation of the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide
Adopt the preparation method of step 1 in embodiment 1, by the 3-in step 1 (4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-formic acid is with the 3-(4-aminomethyl phenyl)-7 that obtains in embodiment 22 step h, mix benzo ring heptene-6-formic acid of 8-dihydro-9-oxy is replaced, and the 3-(2-dimethylamino ethoxy) that (2-diethylin oxyethyl group)-the 4-monomethylaniline obtains with b step in embodiment 17 of the 3-in step 1-4-anisidine is replaced, obtain title compound.1H-NMR(400MHz，CDCl 3)δppm：2.39-2.43(m，9H)，2.86-2.92(m，2H)，3.06-3.09(t，2H)，3.84(s，3H)，4.16-4.22(t，2H)，4.34-4.36(t，2H)，6.82-7.54(m，11H)，7.71(br，1H)；FAB-MS(m/z)：473.1[M+H]+。
Embodiment 39:N-[3-[2-(4-morpholinyl) oxyethyl group]-the 4-p-methoxy-phenyl]-preparation of the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide
Figure S2008100006483D00532
Adopt the preparation method of step 1 in embodiment 1, by the 3-in step 1 (4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-formic acid is with the 3-(4-aminomethyl phenyl)-7 that obtains in embodiment 22 step h, mix benzo ring heptene-6-formic acid of 8-dihydro-9-oxy is replaced, and by 3-[2-(4-morpholinyl) oxyethyl group that (2-diethylin oxyethyl group)-the 4-monomethylaniline obtains with b step in embodiment 18 of the 3-in step 1]-replacement of 4-anisidine, obtain title compound.1H-NMR(400MHz，CDCl 3)δppm：2.39(s，3H)，2.66(m，4H)，2.90-2.93(t，2H)，3.07-3.09(t，2H)，3.76(t，4H)，3.85(s，3H)，4.20-4.24(t，2H)，4.34-4.37(t，2H)，6.83-7.53(m，11H)，7.60(br，1H)；FAB-MS(m/z)：515.1[M+H]+。
Embodiment 40:N-[3-[2-(piperidino) oxyethyl group]-the 4-p-methoxy-phenyl]-preparation of the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide
Adopt the preparation method of step 1 in embodiment 1, by the 3-in step 1 (4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-formic acid is with the 3-(4-aminomethyl phenyl)-7 that obtains in embodiment 22 step h, mix benzo ring heptene-6-formic acid of 8-dihydro-9-oxy is replaced, and by 3-[2-(piperidino) oxyethyl group that (2-diethylin oxyethyl group)-the 4-monomethylaniline obtains with b step in embodiment 19 of the 3-in step 1]-replacement of 4-anisidine, obtain title compound.1H-NMR(400MHz，CDCl 3)δppm：1.44-1.46(m，2H)，1.58-1.64(m，4H)，2.39(s，3H)，2.54(m，4H)，2.83-2.88(t，2H)，3.05-3.08(t，2H)，3.85(s，3H)，4.17-4.21(t，2H)，4.34-4.37(t，2H)，6.82-7.53(m，11H)，7.57(br，1H)；FAB-MS(m/z)：512.9[M+H]+。
Embodiment 41:N-[3-[3-dimethylamino propoxy]-the 4-p-methoxy-phenyl]-preparation of the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide
Adopt the preparation method of step 1 in embodiment 1, by the 3-in step 1 (4-aminomethyl phenyl)-8,9-dihydro-7 H-benzo ring heptene-6-formic acid is with the 3-(4-aminomethyl phenyl)-7 that obtains in embodiment 22 step h, mix benzo ring heptene-6-formic acid of 8-dihydro-9-oxy is replaced, and the 3-that (2-diethylin oxyethyl group)-the 4-monomethylaniline obtains with b step in embodiment 20 of the 3-in step 1 (2-dimethylin propoxy-)-4-anisidine is replaced, obtain title compound.1H-NMR(400MHz，CDCl 3)δppm：2.06-2.11(m，2H)，2.34(s，6H)，2.39(s，3H)，2.57-2.61(t，2H)，3.06-3.09(t，2H)，3.86(s，3H)，4.07-4.12(t，2H)，4.34-4.37(t，2H)，6.8 3-7.5 4(m，11H)，7.71(br，1H)；FAB-MS(m/z)：487.2[M+H]+。
Embodiment 42:N-[3-[2-(1-pyrrolidyl) oxyethyl group]-the 4-p-methoxy-phenyl]-preparation of the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide
Adopt the preparation method of step 1 in embodiment 1, by the 3-in step 1 (4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-formic acid is with the 3-(4-aminomethyl phenyl)-7 that obtains in embodiment 22 step h, mix benzo ring heptene-6-formic acid of 8-dihydro-9-oxy is replaced, and by 3-[2-(1-pyrrolidyl) oxyethyl group that (2-diethylin oxyethyl group)-the 4-monomethylaniline obtains with b step in embodiment 21 of the 3-in step 1]-replacement of 4-anisidine, obtain title compound.1H-NMR(400MHz，CDCl 3)δppm：1.95-1.97(m，4H)，2.38(s，3H)，3.06-3.08(m，6H)，3.23-3.26(t，2H)，3.81(s，3H)，4.32-4.35(m，4H)，6.80-7.60(m，11H)，8.14(br，1H)；FAB-MS(m/z)：499.1[M+H]+。
Embodiment 43:N-[4-[4-(5-hydroxyl-3H-indol-3-yl) piperidin-1-yl methyl] phenyl]-3-(4-aminomethyl phenyl)-8, the preparation of 9-dihydro-7H-benzo ring heptene-6-methane amide
A. 5-benzyloxy-3-(1-benzyl-1.2,3,6-tetrahydropyridine-4-yl)-1H-indoles
Below 5 ℃, 5-benzyloxy indole (5mmol) is being put into to methyl alcohol (10ml) formation suspension; under nitrogen protection, adding mass ratio is 2 5% methanol solution of sodium methylate (20ml); add again 1-benzyl piepridine ketone (5mmol), by this suspension stirring and refluxing 16 hours.After reaction solution is cooling, adds wherein methylene dichloride (16ml) and methyl alcohol (24ml) dilution, and solution is regulated to PH to 5 with Glacial acetic acid, concentrated solution is to the 15ml left and right.In concentrated solution, add water (120ml), use dichloromethane extraction, extraction liquid water and saturated common salt washing, be spin-dried for.The product that obtains is obtained to micro-yellow solid with re-crystallizing in ethyl acetate.1H-NMR(400MHz，DMSO-d 6)δppm：2.76-2.92(m，2H)，3.27-3.79(m，4H)，4.37-4.47(m，2H)，5.08(s，2H)，6.09-7.69(m，15H)，10.91(s，1H)，11.26(s，1H)；FAB-MS(m/z)：395.2[M+H]+。
B. 3-(4-piperidyl)-1H-indoles-5-alcohol
Micro-yellow solid (1mmol) that top step a is obtained is dissolved in anhydrous methanol (7ml), under nitrogen protection, adds 10% palladium carbon and the anhydrous formic acid ammonium (5mmol) of equal quality, and reflux is spent the night.After reaction solution is cooling, add diatomite filtration, and leach thing with chloroform (20ml) washing, merge organic phase, be spin-dried for, obtain yellow solid.1H-NMR(400MHz，DMSO-d 6)δppm：1.82-2.06(m，4H)，2.93-3.34(m，5H)，4.13-4.15(m，1H)，6.61-7.15(m，4H)，8.63(s，1H)，10.59(s，1H)；MS[M]+＝216.2 m/e。
C. 3-[1-(4-nitrobenzyl)-piperidin-4-yl]-1H-indoles-5-alcohol
The yellow solid (0.231mmol) that top step b is obtained is dissolved in acetone (10ml), adds nitrobenzyl bromine (0.231mmol) and triethylamine (0.462mmol), reflux 1 hour.In reaction solution, add water and ethyl acetate, separate organic phase, the water ethyl acetate extraction, merge organic phase, and the product evaporating column separates (eluent: the methylene chloride/methanol system), obtain yellow solid.Micro-yellow solid (1mmol) that top step a is obtained is dissolved in anhydrous methanol (7ml), under nitrogen protection, adds 10% palladium carbon and the anhydrous formic acid ammonium (5mmol) of equal quality, and reflux is spent the night.After reaction solution is cooling, add diatomite filtration, and leach thing with chloroform (20ml) washing, merge organic phase, be spin-dried for, obtain yellow solid.1H-NMR(400MHz，DMSO-d 6)δppm：1.67-1.71(m，2H)，1.87-1.91(m，2H)，2.11-2.19(m，2H)，2.64(m，1H)，2.87-2.91(m，2H)，3.64(s，2H)，4.13-4.15(m，1H)，6.55-8.23(m，8H)，8.56(s，1H)，10.46(s，1H)；MS[M]+＝351.3m/e。
D. 3-[1-(4-aminobenzyl)-piperidin-4-yl]-1H-indoles-5-alcohol
The yellow solid (1mmol) that top step c is obtained is dissolved in tetrahydrofuran (THF) (1ml), drips concentrated hydrochloric acid (2ml) solution of tindichloride (3.22mmol), stirring at room 1 hour.In reaction solution, add tetrahydrofuran (THF) (1ml) and water (1ml), add 30% wet chemical alkalization under 0 ℃, after waiting the solution layering, separate organic phase, water extracts with tetrahydrofuran (THF), merges organic phase.Concentrated rear pillar separates (eluent: the methylene chloride/methanol system), obtain yellow solid.MS[M]+＝321.4m/e。
E. N-[4-[4-(5-hydroxyl-3H-indol-3-yl) piperidin-1-yl methyl] benzene Base]-3-(4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-methane amide
Adopt the preparation method of step 1 in embodiment 1, by the 3-in step 1 (2-diethylin oxyethyl group)-4-monomethylaniline with the 3-[1-that obtains in the steps d of top (4-aminobenzyl)-piperidin-4-yl]-1H-indoles-5-alcohol replaces, and obtains title compound.1H-NMR(400MHz，DMSO-d 6)δppm：1.66-1.72(m，2H)，1.86-1.90(m，2H)，1.99-2.09(m，4H)，2.34(s，3H)，2.61-2.65(m，3H)，2.83-2.93(m，4H)，3.47(s，2H)，6.55-7.70(m，16H)，8.56(s，1H)，10.00(s，1H)，10.46(s，1H)；FAB-MS(m/z)：582.3[M+H]+。
Embodiment 44:N-[4-[4-(3H-indol-3-yl) piperidin-1-yl methyl] phenyl]-3-(4-aminomethyl phenyl)-8, the preparation of 9-dihydro-7H-benzo ring heptene-6-methane amide
Figure S2008100006483D00571
A. 3-(1-benzyl-1,2,3,6-tetrahydropyridine-4-yl)-1H-indoles
Adopt the preparation method of step a in embodiment 43, the 5-benzyloxy indole in step a is replaced with indoles, obtain yellow solid.MS[M]+＝288.4m/e。
B. 3-(4-piperidyl)-1H-indoles
Adopt the preparation method of step b in embodiment 43, by 5-benzyloxy-3-(1-benzyl-1,2 in step b, 3,6-tetrahydropyridine-4-yl)-1H-indoles is with the 3-that obtains in top step a (1-benzyl-1,2,3,6-tetrahydropyridine-4-yl)-1H-indoles is replaced, and obtains yellow solid.MS[M]+＝200.3m/e。
C. 3-[1-(4-nitrobenzyl)-piperidin-4-yl]-the 1H-indoles
Adopt the preparation method of step c in embodiment 43, the 3-in step c (4-piperidyl)-1H-indoles-5-alcohol is replaced with the 3-that obtains in top step b (4-piperidyl)-1H-indoles, obtain yellow solid.1H-NMR(400MHz，CDCl 3)δppm：1.67-1.77(m，2H)，1.91-1.95(m，2H)，2.15-2.21(m，2H)，2.73-2.80(m，1H)，2.88-2.91(m，2H)，3.65(s，2H)，6.9 4-8.22(m，9H)，10.76(s，1H)；MS[M]+＝335.4m/e。
D. 4-[4-(1H-indol-3-yl)-piperidin-1-yl-methyl] aniline
Adopt the preparation method of steps d in embodiment 43, by the 3-[1-in steps d (4-nitrobenzyl)-piperidin-4-yl]-1H-indoles-5-is pure with the 3-[1-that obtains in top step c (4-nitrobenzyl)-piperidin-4-yl]-replacement of 1H-indoles, obtain yellow solid.FAB-MS(m/z)：306.0[M+H]+。
E. N-[4-[4-(3H-indol-3-yl) piperidin-1-yl methyl] phenyl]-3-(4-methylbenzene Base)-8,9-dihydro-7H-benzo ring heptene-6-methane amide
Adopt the preparation method of step 1 in embodiment 1, by the 3-in step 1 (2-diethylin oxyethyl group)-4-monomethylaniline with the 4-[4-that obtains in the steps d of top (1H-indol-3-yl)-piperidin-1-yl-methyl] aniline replaces, and obtains title compound.1H-NMR(400MHz，DMSO-d 6)δppm：1.68-1.74(m，2H)，1.90-2.15(m，6H)，2.34(s，3H)，2.61-2.65(t，2H)，2.72-2.94(m，5H)，3.49(s，2H)，6.92-7.70(m，17H)，9.98(s，1H)，10.77(s，1H)；FAB-MS(m/z)：566.1[M+H]+。
Embodiment 45:N-[4-[4-(5-hydroxyl-3H-indol-3-yl) piperidin-1-yl methyl] phenyl]-preparation of the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide
Figure S2008100006483D00591
Adopt the preparation method of step 1 in embodiment 1, by the 3-in step 1 (4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-formic acid is with the 3-(4-aminomethyl phenyl)-7 that obtains in embodiment 22 step h, mix benzo ring heptene-6-formic acid of 8-dihydro-9-oxy is replaced, and by the 3-[1-(4-aminobenzyl) that (2-diethylin oxyethyl group)-the 4-monomethylaniline obtains with d step in embodiment 43 of the 3-in step 1-piperidin-4-yl]-1H-indoles-5-alcohol replacement, obtain title compound.1H-NMR(400MHz，DMSO-d 6)δppm：1.66-1.72(m，2H)，1.86-1.90(m，2H)，1.99-2.09(m，4H)，2.34(s，3H)，2.61-2.65(m，1H)，2.83-2.93(m，2H)，3.47(s，2H)，3.98-4.11(m，2H)，6.55-7.70(m，16H)，8.56(s，1H)，10.00(s，1H)，10.46(s，1H)；FAB-MS(m/z)：584.3[M+H]+。
Embodiment 4 6:N-[4-[4-(3H-indol-3-yl) piperidin-1-yl methyl] phenyl]-the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide;
Figure S2008100006483D00592
Adopt the preparation method of step 1 in embodiment 1, by the 3-in step 1 (4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-formic acid is with the 3-(4-aminomethyl phenyl)-7 that obtains in embodiment 22 step h, mix benzo ring heptene-6-formic acid of 8-dihydro-9-oxy is replaced, and by the 4-[4-(1H-indol-3-yl) that (2-diethylin oxyethyl group)-the 4-monomethylaniline obtains with d step in embodiment 44 of the 3-in step 1-piperidin-1-yl-methyl] the aniline replacement, obtain title compound.1H-NMR(400MHz，DMSO-d 6)δppm：1.68-1.74(m，2H)，1.90-2.15(m，6H)，2.34(s，3H)，2.72-2.94(m，3H)，3.49(s，2H)，3.98-4.11(m，2H)，6.92-7.70(m，17H)，9.98(s，1H)，10.77(s，1H)；FAB-MS(m/z)：568.1[M+H]+。
The HIV-1 of the compound that the present invention relates to suppresses activity and can detect with the following method:
Embodiment 47: the HIV (human immunodeficiency virus)-resistant activity evaluation of the compounds of this invention
For the external Anti-HIV-1 Active of compound in the TZM-b1 cell that the present invention relates to, 50 μ l compounds are mixed with to the solution of different concns, with the virus strain of equal volume, infect (infection multiplicity is 0.01), 37 ℃ of hatching 30min.Three groups of each concentration difference parallel laboratory tests.This mixture is joined to the 100 μ lTZB-b1 cells (1 * 10 that spent the night with 37 ℃ of pre-treatment of luciferase on 96 orifice plates 5) in, cultivated three days for 37 ℃.By lysis and with luminoscope (Ultra386, Tecan, Durham, NC), measure uciferase activity.The IC of the per-cent inhibiting rate of cytogamy 50(half-inhibition concentration) value is by the CalcuSyn computed in software, and this software is provided by Sloan-Kettering Cancer Center (New York).
Embodiment 48: the Cytotoxic evaluation of the compounds of this invention
100 μ l solution of each compound add the TZM-bl cell (5 * 10 of same volume in certain concentration on 96 well culture plates 5/ ml), 37 ℃ of hatchings, after 4 days, add 50 μ l XTT solution (1mg/ml) and 0.02nM PMS.Hatch after 4 hours, with the BLISA detector, at the 450nm place, detect and absorb, CC 50(the poisonous concentration of half) value is used the Calcusyn computed in software, and this software is provided by Sloan-Kettering Cancer Center (New York).
The In Vitro Anti HIV of the HIV-1 of part embodiment compound suppresses active (IC 50) and cytotoxicity (CC 50) be shown in table 1.
Table 1
No. embodiment IC 50(μM) CC 50(μM)
13 0.05 7±0.028 3.32±0.35
22 0.50±0.041 8.32±1.16
32 2.23±0.74 39.52±7.10
33 2.38±0.50 6.38±3.02
37 0.068±0.032 1.59±0.51
44 1.18±0.18 8.45±0.65

Claims (8)

1. the compound that has following general formula I a, its raceme or optically active isomer or its pharmacologically acceptable salt,
Figure FSB0000112982610000011
Ia
Wherein:
X is-CH 2-or-0-;
R1 is C 1-C 6The phenyl ring that-alkyl replaces;
N is 0～3 integer;
R2 and R3 are selected from hydrogen, C independently of one another 1-C 6-alkyl; Perhaps R2 forms 5～6 rings jointly with the nitrogen-atoms that R3 is connected with it;
R4 is hydrogen; Halogen; Carboxyl; Nitro; Cyano group; C 1-C 6-alkyl; Hydroxyl; C 1-C 6-alkoxyl group; Sulfydryl; C 1-C 6-alkylthio, wherein optional sulfinyl or the alkylsulfonyl of being oxidized to of sulphur atom; Amino; Acyl group or esterifying carboxyl group.
2. the compound of claim 1, it is selected from:
N-[3-(2-diethyl amino base oxethyl)-4-aminomethyl phenyl]-3-(4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-methane amide;
N-[3-(2-diisopropylaminoethyl oxyethyl group)-4-aminomethyl phenyl]-3-(4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-methane amide;
N-[3-(2-dimethylamino ethoxy)-4-aminomethyl phenyl]-3-(4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-methane amide;
N-[3-[2-(4-morpholinyl) oxyethyl group]-the 4-aminomethyl phenyl]-3-(4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-methane amide;
N-[3-[2-(piperidino) oxyethyl group]-the 4-aminomethyl phenyl]-3-(4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-methane amide;
N-3-the 3-dimethylamino propoxy]-the 4-aminomethyl phenyl ］-3-(4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-methane amide;
N-3-[2-(1-pyrrolidyl) oxyethyl group]-the 4-aminomethyl phenyl]-3-(4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-methane amide;
N-[3-(2-diethyl amino base oxethyl) phenyl]-3-(4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-methane amide;
N-[3-(2-diisopropylaminoethyl oxyethyl group) phenyl]-3-(4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-methane amide;
N-[3-(2-dimethylamino ethoxy) phenyl]-3-(4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-methane amide;
N-[3-[2-(4-morpholinyl) oxyethyl group] phenyl]-3-(4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-methane amide;
N-[3-[2-(piperidino) oxyethyl group] phenyl]-3-(4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-methane amide;
The N-[3-[3-dimethylamino propoxy ］ phenyl]-3-(4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-methane amide;
N-[3-[2-(1_ pyrrolidyl) oxyethyl group] phenyl]-3-(4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-methane amide;
N-[3-(2-diethyl amino base oxethyl)-4-p-methoxy-phenyl]-3-(4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-methane amide;
N-[3-(2-diisopropylaminoethyl oxyethyl group)-4-p-methoxy-phenyl]-3-(4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-methane amide;
N-3-(2-dimethylamino ethoxy)-4-p-methoxy-phenyl]-3-(4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-methane amide;
N-3-2-(4-morpholinyl) oxyethyl group]-the 4-p-methoxy-phenyl]-3-(4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-methane amide;
N-3-[2-(1_ piperidyl) oxyethyl group]-the 4-p-methoxy-phenyl]-3-(4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-methane amide;
N-3-the 3-dimethylamino propoxy]-the 4-p-methoxy-phenyl]-3-(4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-methane amide;
N-3-2-(1-pyrrolidyl) oxyethyl group]-the 4-p-methoxy-phenyl]-3-(4-aminomethyl phenyl)-8,9-dihydro-7H-benzo ring heptene-6-methane amide;
N-[3-(2-diethyl amino base oxethyl)-4-aminomethyl phenyl]-the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide;
N-3-(2-diisopropylaminoethyl oxyethyl group)-4-aminomethyl phenyl]-the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide;
N-[3-(2-dimethylamino ethoxy)-4-aminomethyl phenyl]-the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide;
N-[3-[2-(4-morpholinyl) oxyethyl group]-the 4-aminomethyl phenyl]-the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide;
N-[3-2-(piperidino) oxyethyl group]-the 4-aminomethyl phenyl]-the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide;
N-［ 3-[3-dimethylamino propoxy ］-4-aminomethyl phenyl]-the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide;
N-[3-[2-(1-pyrrolidyl) oxyethyl group ］-the 4-aminomethyl phenyl ］-the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide;
N-3-(2-diethyl amino base oxethyl) phenyl]-the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide;
N-[3-(2-diisopropylaminoethyl oxyethyl group) phenyl ］-the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide;
N-[3-(2-dimethylamino ethoxy) phenyl]-the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide;
N-［ 3-[2-(4-morpholinyl) oxyethyl group ］ phenyl]-the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide;
N-[3-[2-(piperidino) oxyethyl group] phenyl]-the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide;
The N-[3-[3-dimethylamino propoxy ］ phenyl]-the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide;
N-[3-[2-(1-pyrrolidyl) oxyethyl group] phenyl]-the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide;
N-3-(2-diethyl amino base oxethyl)-4-p-methoxy-phenyl]-the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide;
N-[3-(2-diisopropylaminoethyl oxyethyl group)-4-p-methoxy-phenyl]-the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide;
N-[3-(2-dimethylamino ethoxy)-4-p-methoxy-phenyl]-the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide;
N-[3-[2-(4-morpholinyl) oxyethyl group]-the 4-p-methoxy-phenyl]-the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide;
N-[3-[2-(piperidino) oxyethyl group]-the 4-p-methoxy-phenyl]-the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide;
N-3-the 3-dimethylamino propoxy]-the 4-p-methoxy-phenyl]-the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide; With
N-[3-2-(1-pyrrolidyl) oxyethyl group]-the 4-p-methoxy-phenyl]-the assorted benzo ring heptene of 3-(4-aminomethyl phenyl)-7,8 dihydro-9-oxies-6-methane amide;
Its raceme or optically active isomer or pharmacologically acceptable salt.
3. the method for preparing the described compound of claim 1 or 2 or its raceme or optically active isomer or pharmacologically acceptable salt, it comprises,
For general formula I a compound, wherein R1, R2, R3, R4, X, n have definition as claimed in claim 1 or 2:
1) raw material 1 and the reaction of R1-alkylating reagent, the tetrahydro benzo suberene that generation R1 replaces-5-ketone (general formula 2)
A. when X is methylene radical, under the Lewis acid effect, F-K reaction occurring with bromobenzene and glutaric acid monoester acyl chlorides, generates 4-to the Brombenzyl butyric ester; Through hydrolysis, reducing carbonyl and cyclization, generate intermediate 1 again;
B. when X is oxygen, with p bromophenol, directly with 4-bromo-butyric acid ethyl ester, under the alkali effect, react, generate 4-to bromine phenoxy group methyl-butyrate, then through hydrolysis, reducing carbonyl and cyclization generation intermediate 1:
Figure FSB0000112982610000051
1 2
The compound of the formula 2 that 2) step 1 is obtained carries out nucleophilic substitution, at ketone carbonyl ortho position, introduces methoxycarbonyl, and then the reductone carbonyl is hydroxyl, then through eliminating and be hydrolyzed the intermediate that obtains the general formula II;
Figure FSB0000112982610000053
Ⅱ
3) starting raw material 3 and the hydrochloride of starting raw material 4 are reacted under the alkali effect, the nitro-compound of generation, through reduction, obtains the intermediate of general formula III:
Figure FSB0000112982610000054
3 4 Ⅲ
4) carboxyl of intermediate II is converted into to acyl chlorides, then reacts with the intermediate III, obtain I a compounds.
4. pharmaceutical composition, it contains the described compound of claim 1 or 2 or its raceme or optically active isomer or pharmacologically acceptable salt, and at least a pharmaceutically acceptable carrier, thinner or vehicle.
5. claim 1 or 2 compound or its raceme or optically active isomer or pharmacologically acceptable salt are for the preparation for the treatment of or the purposes of preventing the medicine of the mammiferous disease relevant with the CCR5 activity or illness.
6. the purposes of claim 5, wherein, described disease or the illness relevant to the CCR5 activity are selected from AIDS, sacroiliitis, inflammatory bowel, atopic dermatitis, psoriasis, asthma, multiple sclerosis, solid organ transplantation repulsion, graft versus host disease (GVH disease), Alzheimer, local anaphylaxis, arteriosclerosis, meat shape knurl disease, chronic obstructive pulmonary disease, ephrosis, diabetes, sarcoidosis, fibrosis and atherosclerosis.
7. the purposes of claim 6, wherein said sacroiliitis is rheumatoid arthritis.
8. the purposes of claim 6, wherein said ephrosis is ephritis.
CN2008100006483A 2008-01-11 2008-01-11 Benzo cyclohepten derivate, and preparation and medical use thereof Expired - Fee Related CN101481323B (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN2008100006483A CN101481323B (en) 2008-01-11 2008-01-11 Benzo cyclohepten derivate, and preparation and medical use thereof
PCT/CN2009/000040 WO2009092284A1 (en) 2008-01-11 2009-01-12 Benzocycloheptene derivatives, preparing processes and pharmaceutical uses thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN2008100006483A CN101481323B (en) 2008-01-11 2008-01-11 Benzo cyclohepten derivate, and preparation and medical use thereof

Related Child Applications (1)

Application Number Title Priority Date Filing Date
CN201210249256.7A Division CN102796075B (en) 2008-01-11 2008-01-11 Benzocycloheptenes derivative as well as preparation method and medical application thereof

Publications (2)

Publication Number Publication Date
CN101481323A CN101481323A (en) 2009-07-15
CN101481323B true CN101481323B (en) 2013-11-20

Family

ID=40878636

Family Applications (1)

Application Number Title Priority Date Filing Date
CN2008100006483A Expired - Fee Related CN101481323B (en) 2008-01-11 2008-01-11 Benzo cyclohepten derivate, and preparation and medical use thereof

Country Status (2)

Country Link
CN (1) CN101481323B (en)
WO (1) WO2009092284A1 (en)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9062076B2 (en) * 2009-10-22 2015-06-23 Fibrotech Therapeutics Pty Ltd Fused ring analogues of anti-fibrotic agents
US11014873B2 (en) 2017-02-03 2021-05-25 Certa Therapeutics Pty Ltd. Anti-fibrotic compounds
CN108675933A (en) * 2018-05-09 2018-10-19 青岛科技大学 N, N- diethyl -2- (2- methoxyl group -5- nitro-phenoxies)-ethamine and its preparation method and application
CN112851624A (en) * 2019-11-12 2021-05-28 云南大学 Synthetic method of 2-benzoxazepine compound
US20230382860A1 (en) * 2020-10-19 2023-11-30 Council Of Scientific And Industrial Research Bioactive Benzocycloheptene Analogues From Himachalenes and its Applications
CN114907288B (en) * 2022-05-13 2023-12-08 中国医学科学院医药生物技术研究所 Application of nitrobenzene compounds in preparation of pseudomonas aeruginosa quorum sensing inhibitor

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1282326A (en) * 1997-12-19 2001-01-31 武田药品工业株式会社 Anilide derivative, production and use thereof
CN1282243A (en) * 1997-12-19 2001-01-31 武田药品工业株式会社 Pharmaceutical composition for antagonizing CCR5 comprising anilide derivative

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2000128842A (en) * 1998-08-20 2000-05-09 Takeda Chem Ind Ltd Quarternary ammonium salt derivative and its application
AU4145200A (en) * 1999-05-07 2000-11-21 Takeda Chemical Industries Ltd. Cyclic compounds and uses thereof
KR101229416B1 (en) * 2004-06-25 2013-02-05 얀센 파마슈티카 엔.브이. Quaternary salt ccr2 antagonists

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1282326A (en) * 1997-12-19 2001-01-31 武田药品工业株式会社 Anilide derivative, production and use thereof
CN1282243A (en) * 1997-12-19 2001-01-31 武田药品工业株式会社 Pharmaceutical composition for antagonizing CCR5 comprising anilide derivative

Also Published As

Publication number Publication date
CN101481323A (en) 2009-07-15
WO2009092284A1 (en) 2009-07-30

Similar Documents

Publication Publication Date Title
CN102264707B (en) Bicyclic heterocyclic compound
DE60223715T2 (en) GLYT1 TRANSPORTER INHIBITORS AND THEIR USE IN THE TREATMENT OF NEUROLOGICAL AND NEUROPSYCHIATIVE DISEASES
DK2152258T3 (en) Derivatives of fluorene, anthracene, xanthene, acridine dibenzosuberone AND DERIVATIVES AND USES
DE69108138T2 (en) Imidazopyridine derivatives and their use.
CN101481323B (en) Benzo cyclohepten derivate, and preparation and medical use thereof
JPH08502275A (en) 5-HT 4) Heterocyclic Fused Benzoic Acid Derivatives for Receptor Antagonists
BG107460A (en) Benzimidazole derivatives, preparation and therapeutic use thereof
ES2874352T3 (en) Aryl heterocyclic piperidinone agonists of formylated peptide receptor 1 and formylated peptide receptor 2
CA3085353A1 (en) Quinazolinones as parp14 inhibitors
KR102012222B1 (en) Benzoxazinone amides as mineralocorticoid receptor modulators
ES2869129T3 (en) Formylated peptide receptor 2 piperidinone agonists
BR112016007329B1 (en) compound, pharmaceutical composition, and, use of a compound for the manufacture of a drug for the treatment of cancer, autoimmune diseases or viral diseases
KR20240049561A (en) Benzazepine aromatic ring derivatives and their applications in medicine
ES2594252T3 (en) Quinolone compound and pharmaceutical composition
AU2017201415C1 (en) Process for the preparation of c-fms kinase inhibitors
EP2865678A2 (en) Crystalline hemi-tartrate form of a benzoimidazol-2-yl pyrimidine derivative
JPH0523269B2 (en)
TW202233620A (en) Cftr modulator compounds, compositions, and uses thereof
KR0163413B1 (en) Neuroleptic perhydro-1h-pyrido[1,2-a]pyrazines
CN102796075B (en) Benzocycloheptenes derivative as well as preparation method and medical application thereof
BR112019026955A2 (en) dihydro-pyrrole-pyridine derivatives
HUT71488A (en) Process for the production of neuroleptic 2-substituted perhydro-1-h-pyrido[1,2a]pyrazines and pharmaceuticals compositions containing the same
JP2012012388A (en) Pharmaceutical agent
KR880001715B1 (en) Process for preparing 1-furyl-3,4-dihydro-isoquinolines
EP1572690A1 (en) Thiazole compounds as integrin receptor antagonists derivatives

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20131120

Termination date: 20200111

CF01 Termination of patent right due to non-payment of annual fee